European Journal of Endocrinology 10.1530/EJE-16-0616 imbalance betweenexcessiveformationofoxidants Hence, oxidativestresswasintroducedtodefinethe and nucleicacids;compromisecellviability( interrupt oxidativeequilibrium;damageproteins,lipids unfavorable cellularconditions,oxygenderivativescan Living organismscannotexistwithoutoxygen;yetunder gradually highlightedasanintegralpartofaerobiclife( Oxidative metabolismandredoxhomeostasishavebeen Introduction active mediatorofvariousmetabolicandreproductivedisorders. background, canpotentiallycompromisenormalmetabolicandreproductivefunctionsinwomenmayact as an account, nutritionanditsaccompanyingpostprandialoxidativestress,intheuniquecontextoffemalehormonal violate delicateoxidativebalancethatismandatorytosecurenormalreproductivefunction.Taken alltheaboveinto secretion takeplace.Simultaneously, inreproductivetissues,nutrition-inducedoxidativestresscanpotentially subclinical inflammation,endothelialdysfunction,mitochondrialderegulationandimpairedinsulinresponse and orchestrated inthemainmetabolicorgans,includingadiposetissue,skeletalmuscle,liverandpancreas,where in thepostprandialstate,alteringmetabolicstateoftissues.Adominounfavorablechangesis hormonal balance.Nutrientingestionpromotesamajorinflammatoryandoxidativeresponseatthecellularlevel Nutrition cangenerateoxidativestressandtriggeracascadeofmoleculareventsthatdisrupt Abstract Unit, 3rdDepartmentofInternalMedicine,UniversityAthensMedicalSchool,Athens,Greece 1 Georgia Kassi Evanthia Diamanti-Kandarakis metabolic andreproductive disorders inwomen Nutrition asamediatorofoxidativestress in MECHANISMS INENDOCRINOLOGY Department ofEndocrinologyandDiabetesCenterExcellence,EUROCLINIC,Athens,Greece DOI: 10.1530/EJE-16-0616 www.eje-online.orgwww.eje-online.org aspects ofmetabolicandreproductive abnormalitiesinpolycysticovariansyndrome. Greece. Her research interests havefocused for the last 25years on clinical, molecular and environmental the ChairmanofDepartment ofEndocrinologyandDiabetesCenterExcellence,EUROCLINIC, Athens, Dr EvanthiaDiamanti-Kandarakis Invited Author’s profile Review

2 © 2017EuropeanSocietyof Endocrinology © 2016EuropeanSociety ofEndocrinology 1 and others E Diamanti-Kandarakis , Olga Papalou isaProfessorofInternalMedicine–EndocrinologyandMetabolism and Printed inGreatBritain 1 , EleniA Kandaraki

2 1 ). ). ).

stress. Macronutrients can be inflammatory and possibly andpossibly stress. Macronutrientscanbeinflammatory body, suchasnutrition,canpotentiallygenerate oxidative physiological conditions,normalfunctionsofhuman plethora ofhumandiseases( oxidative stressliesinthepathophysiologicalcoreof a human body( in thepresenceoflimitedantioxidantdefenses Nutrition andoxidativestress Published byBioscientifica Ltd. There is an increasing body of evidence showing that There isanincreasingbodyofevidenceshowingthat 2 and 3 ). 2 Endocrine Downloaded fromBioscientifica.com at09/26/202101:56:54AM 4 , 5 , (2017) Endocrinology European Journal of gmail.com e. Email to EDiamanti-Kandarakis should beaddressed Correspondence 6 176 diamanti.kandarakis@ ). However, evenunder 176 : 2 176 :2 , R79–R99

R79 –R99 via freeaccess European Journal of Endocrinology www.eje-online.org ( adenine dinucleotideandflavinmononucleotide(FMN) of catalyticcofactors,tetrahydrobiopterin(BH4),flavin of nitricoxidesynthase (NOS) and under thepresence is synthesizedfrom derive fromnitricoxide(NO)( generating eventuallysuperoxide(O a tendencyforanelectrontodirectlypassoxygen, mitochondrial electrontransportchain(ETC),thereis to betheprincipalsource ofROS.Specifically, inthe ( activation takesplaceviadifferentcellularprocesses singlet oxygenandhydrogenperoxide(H superoxide anion(O formed uponincompletereactionofoxygen,including species (RNS).ROSderivefrommolecularoxygen, reactive oxygenspecies(ROS)andnitrogen There are two main classes of free radicals or oxidants: oxidative metabolism Elements offundamentals of variousmetabolicandreproductivedisturbances( and thereforecouldbeinvolvedinthepathophysiology subclinical inflammationandendothelialdysfunction Postprandial oxidativestresshasbeencloselylinkedto of excessorinadequatesupplywithnutrients( load andtheantioxidantdefenseasaconsequence postprandial state of imbalance between the pro-oxidant oxidative stress – has been introduced to describe the pro-oxidant ( 15 i. 1 Fig. Review ). Undercertainstimuli,NOreactswithsuperoxide RNS areafamilyofchemicalcompoundsthat ) ( 12 ). However, mitochondriaareconsidered 7 ). A new term – nutritional or postprandial ). Anewterm–nutritionalorpostprandial l -arginine, viathecatalyticaction 2 − ), hydroxylradical(OH 14 and others E Diamanti-Kandarakis ). Physiologically, NO 2 − ) (

13 2 ). O 2 ) ( 11 − ). This ) and 9 , 10

8 ). ). oxidase ( ROS generation, as well as to the activation of NADPH (RAGE) activatesNF- multiligand receptorforadvancedglycationendproducts via multiplemechanisms( their formation,AGEspromoteROSandRNS as well as from absorbed exogenous sources ( endogenous nonenzymaticglycationofmacromolecules, group ofmorethan20differentcompounds,derivedfrom AGEs. AGEs,orglycotoxins,constituteaheterogenous properties are share truly pro-oxidant and inflammatory other moleculesthathavealsobeenacknowledgedto trioxide (N of RNS,suchasnitrogendioxide(·NO and canfurtherpromotetheproductionofotherforms to be one of the most toxic RNS produced in human body (O system ofthebody, oxidative stressdominates ( compensated bythepowerfulantioxidantdefense pro-oxidants ( vitamin E,selenium(Se)andzinc(Zn),usedtoterminate such asglutathione,thioredoxin,vitaminC,A, antioxidants areexogenousandendogenousmolecules, glutathione peroxidase(GPx)( including superoxide dismutase (SOD), catalase (CAT) and key enzymesthatcandetoxifyexcessiveROSandRNS, nonenzymatic. Enzymaticantioxidantsconstituteinnate, be dividedintotwomajorcategories:enzymaticand to maintainoxidativeequilibrium( Nutrition andoxidativestress 2 − Antioxidants aretheopposingforce ofhumanbody In addition to the above mentioned pro-oxidants, When overproduction of free radicals cannot be ) generatingperoxynitrite(ONOO 19 2 , O 20 3 13 ) ( ). 16 , 23 ONOO superoxide anion;OH species; ROS,reactiveoxygen O nitric oxide;RNS,reactivenitrogen adenine dinucleotidephosphate; NO, hydrogen peroxide;NADPH,nicotinamide GSSG, glutathionedisulfide;H mononucleotide; GSH,glutathione; flavin adeninedinucleotide;FMN, endothelial nitricoxidesynthase;FAD, (BH4, tetrahydrobiopterin; ENOS, different enzymaticreactions production andclearancevia Molecular pathwaysofROSandRNS Figure 1 ). ). κ B, whichinturnleadstoincreased Downloaded fromBioscientifica.com at09/26/202101:56:54AM − , peroxynitrite). 18 ). BindingofAGEstotheir 22 ), whereasnonenzymatic Fig. 2 176 − − ), whichisbelieved , hydroxylradical; 2 :2 ) anddinitrogen ) ( 21

). Theycan 2 O 17 2 , ). Upon 24

R80 ) and 2 via freeaccess − : European Journal of Endocrinology ROS, reactiveoxygenspecies;RSNO,S-nitrosothiol). radical; ONOO peroxide; NO (AGEs, advancedglycationendproducts;H complementary, interconnectedandgiverisetoeachother human body, astheseoppositeforcesareactually Pro-oxidants andantioxidantsrepresentthe‘yinyang’of Figure 2 environmental stimuli, there is an increasing share of that earlylifedevelopment iscriticallysensitiveto of healthanddiseases’hypothesis, whichpostulates Since theestablishmentof the‘Developmentalorigins Nutrition triggersoxidativestress earlyinlife oxidative stress Nutrition isamajormodulatorof oxidative stressandalterbody’s homeostasis( for thehumanbodythatcanpostprandiallytrigger andpro-oxidant stimuli themselves canbeinflammatory ( between caloricintakeandlow-gradeinflammation Since theestablishmentofbidirectionalassociation physiological functionsofhumanbody, suchasnutrition. variety ofdiseases( of oxidativestressnotonlyinthepathophysiologya pathways has led scientific society to investigate the role This activeimplicationofROSinmultiplemolecular ROS initiatemultiplemolecularpathways( 32 Review ), a crucial query emerged whether macronutrients ), a crucial query − , nitroxyl;O − , peroxynitrite;RNS,reactivenitrogenspecies; 5 , 27 2 , − 28 , superoxideanion;OH , 29 , 30 and others E Diamanti-Kandarakis , 31 ) butalsoinnormal 2 O 2 , hydrogen

12 33 − , hydroxyl , ). 25 , 26

). gestation, but not during postweaning period ( malnutrition, obesityorobesogenicmaternaldietduring through variousexperimentalmodels( mediator ofnutrition-inducedepigeneticchanges compromised fertilitylaterinlife( at anincreasedriskforcardiometabolicdisordersand context ofaprenatallyrichnutritionalenvironmentare adulthood ( cardiovascular diseaseandreproductivedysregulationin linked toincreasedriskforobesity, insulinresistance, with earlycatch-upgrowthduringinfancyhasbeen undernutrition has been extensively studied ( promoter oftheseintrauterineepigeneticmodifications health anddisease. during earlyhumandevelopmentcanaffecttheriskfor literature focusingonhowenvironmentalfactorsacting evaluating arealmixedmeal inhealthysubjects,acute comparison withglucoseand lipids( oxidative ROSformationbut toamuchlesserextentin persistent, whereasprotein (cysein) intakealsoincreased to thatofglucoseingestion butmoreprolongedand ROS generationbyleukocytes,similarinmagnitude ingestion ofsaturatedfat(cream)ledtoanincrease in lipid andproteinintakewerealsopublished.Acute intake bynormalsubjects( mononuclear (MNC)leukocyteswasafterglucose ROS generationbypolymorphonuclear(PMN)and that amacronutrientinducesinflammationand byMohanty The initialobservation Nutrition andoxidativestress atthecellularlevel disorders inadulthood. evolving riskfactorformetabolicaswellreproductive pathways, including generation of oxidative stress, an development caninduceepigeneticchanges,viadifferent during thecriticalperiodsofprenatalandperinatal definitive conclusionsbeestablished.However, nutrition experimental models,andthereisalongwayuntil domain ofdevelopmentalprogrammingoriginatesfrom their offspring( accompanied byasignificantattenuationofadiposityin Simultaneously, antioxidant supplementation was making themvulnerabletodiabetogeniceffects( and impairedantioxidantcapacityintheoffspring, was associatedwithincreased oxidative stressmarkers Nutrition andoxidativestress Oxidative stress hasbeen proposed as a potential Among environmentalfactors,nutritionasapotent Currently, themajorityofevidenceregarding 35 , 44 in utero 36 ). , 37 ). Likewise,offspringraisedinthe andlowbirthweight,combined Downloaded fromBioscientifica.com at09/26/202101:56:54AM 45 ). Analogousfindingsfor 38 , 176 et al. 39 34 46 www.eje-online.org :2 ). ). Specifically, ). Furthermore, demonstrating 40 ). Maternal 42 R81 , 43 41 via freeaccess ). ), European Journal of Endocrinology www.eje-online.org reproductive disorders. oxidative statehasbeenlinked withmetabolicand mitochondria. Incessantpropagation ofthispostprandial stress originatesfromtwomajor sources:leukocytesand consumption andcookingmethods. Postprandialoxidative of calorieintake,typemicronutrients,antioxidantnutrient which ismodulatedviadifferent co-existingfactors:amount Food ingestioninducesoxidativestress,themagnitudeof Figure 3 factors ( and mitochondria,canbemodulatedbyseveralcoexisting formation andgeneration,originatingfromleukocytes supply of antioxidant nutrients ( consequence ofexcessoxidativeloadorinadequate the pro-oxidantloadandantioxidantdefenseasa describe thepostprandialstateofimbalancebetween postprandial oxidativestress–hasbeenintroducedto p47 proteinsIKK the expressionofinhibitory I changesweredetected,withadecreasein inflammatory κ B Review α phox Im Therefore, a new term – dietary ornutritional Therefore, anewterm–dietary andanincreaseinNF- pair Leukocytes subunit( Metabolic and Fig. 3 ed insulin secr Postprandial oxidativestr ). etio Infla 3. re Mitochondria-independent: n sponse 47 In 1. mma inflam cr 2. ). Intracellula eased ROSpr accu

Activation of tion/endothelial and ma re mu tory lation pr r cascades lipid oduction oductive disorders κ

B binding,plasmaCRPand Disruption of

Mitochondria dysfunction

and others E Diamanti-Kandarakis 8 ). Postprandially, ROS 2. 3. 1. in Mitochondria-dependent: De In ovar Decr oxidative ess cr re α eased eased gulated andIKK y gene expr AT ROS pr mi m P lieu itochondrial ession pr oduction oduction

β

, and

lipid consumptionevokesequaloxidativeresponses oxidative stress.Asmentionedabove,carbohydrateand is also catalyticin the amplitude of postprandial protein carbonylation( in ROSgenerationbyleukocytes,lipidperoxidationand in whichcaloricrestrictionledtoarespectabledecrease affected bythecaloricamount,asindicatedstudies from mitochondria,ROSgenerationbyleukocytesisalso superoxide anionsenterthecirculation ( to molecularoxygen.Asaresult,moreand eventually leadingtoincreasedtransferofsingleelectrons capacity of mitochondria for oxidative phosphorylation, concentrations ofglucoseandFFA outpacethetotal free fattyacids(FFA) inbloodcirculation. Theseample in abnormalsurges in blood glucose, triglycerides and stress. Excessiveamountofhigh-caloriefoodresults affecting theintensityofpostprandialoxidative ROS generationinthepostprandial state.Therefore, presence of obesity or physical inactivity, can also affect increase inLDLsusceptibility tooxidation( meal-induced oxidative stress and mitigate the postprandial against atherosclerosisandCVD,wasalsoshowntoprevent red wine,whichisestablishedtohaveaprotectiveeffect geneexpression( proinflammatory total inhibitionofROSgenerationandadecrease in a stressinnormal subjects,with and inflammatory meal wasshowntopreventthemeal-inducedoxidative when combinedwithahigh-fat,high-carbohydrate postprandial state.Forexample,orangejuiceintake nutrients canalsoinfluencetheoxidativemilieuin concentration ofNF- resulted inamoreavidactivationofMNCsandincreased of highglycemicindexcarbohydratesbyhealthysubjects were reportedintermsofglycemicindex,asconsumption carbohydrates, differencesinpostprandialoxidativestress feeding scenario( cytokines oradetrimentaleffectofSFA inanacute PUFA-rich mealsonpostprandialplasmainflammatory to proveclearbeneficialeffectoftheconsumption However, and have failed scientific dataare contradictory effect( are knowntoexertananti-inflammatory linked toCVD,whereasn-3polyunsaturatedfats(PUFA) inflammation, assaturatedfats(SFA) havebeenclosely consumed mayhavearoleintheimmediatepostprandial a moreprolongedone.Regardinglipids,thetypeoffat by leukocytes,exceptforthefactthatlatterevokes Nutrition andoxidativestress Furthermore, thetypeofmicronutrientsconsumed The amountofcaloricintakeisadecisivefactor Lifestyle characteristicsof an individual,suchas Consumption ofantioxidantandanti-inflammatory 55 κ B ( , 50 Downloaded fromBioscientifica.com at09/26/202101:56:54AM 57 56 , 51 ). ). Simultaneously, regarding , 52 ). 58 ). In a similar setting, ). Inasimilarsetting, 176 10 :2 59 , 48 , 60 , 49 , 53 61 ). Apart R82 , ). 54 via freeaccess ). European Journal of Endocrinology cycle ( oxidative stress and ultimately initiate an endless vicious tissues interactingwithnutrients willfurtheraggravate pancreatic tissues includingadiposetissue, skeletalmuscle,liverand orchestrates adominoofmetabolicchangesindifferent stress, aftercarbohydrate,lipidandproteinintake, metabolic statusofthetissues.Postprandialoxidative oxidative responseatthecellularlevelaltering and Nutrient ingestiontriggersamajorinflammatory tissues level Nutrition andoxidativestress atthemetabolic disorders inwomenaswell. to thepathophysiologyofmetabolicandreproductive state thatcharacterizesmodernlifestylemaycontribute these derangementsduringthecontinuouspostprandial factors invariousdiseases.Incessantaccumulationofall are slowlygainingimportantattentionasmajorrisk hyperlipidemia, orso-calledpostprandialdysmetabolism, postprandial state.Indeed,hyperglycemiaand and oxidative derangements in the major inflammatory body ofevidenceindicatingthatnutritioninduces BMI changes( improvement oftheirhormonalprofile,independent of alipaseinhibitor(orlistat)ledtorespectable AGE dietinconjunctionwith6-monthadministration our group in womenwithPCOS,itwasshownthatlow- on reproductivedisturbedwomen,aswell.Inastudyby subjects ( flow-mediated dilatationbothinhealthyanddiabetic dysfunction, as depicted by asignificant decreasein AGEs (coke)resultedpostprandiallyinacuteendothelial Uribarri AGEs( temperature leadtoformationofdietary high inproteinandfat,cookedshortlyunder impact onoxidativemetabolismpostprandially. Foods, postprandial oxidativestress( failed todisplayabeneficialeffectoftrainingstatusinthe endogenous antioxidantdefenses,variousresearches have exercise isconsideredasapowerfultoolofupregulating its effectinpostprandialoxidativestress.Although dataprevailintheliteratureconcerning contradictory non-obese healthyindividuals( stress inresponsetoahigh-fatmealcomparisonwith experience anexaggeratedandmorepersistentoxidative as depictedinastudybyBloomer Review Taken alltheaboveintoaccount,thereisalarge Finally, cookingmethodscanalsohaveanaggravating Fig. 4 t al et 66 β ). Dietary AGEsseemtohaveanegativeimpact ). Dietary ). -cells. These active but metabolically disturbed . showedthatasingleoralchallengeby 67 ). 63 , and others E Diamanti-Kandarakis 62 64 ). Regardingexercise, , t al. et 65 ). , obesesubjects

12

). ). box proteinO1,IL-6:Interleukin6,MCP-1:Monocyte tissues level(ER:endoplasmicreticulum,FoxO1:Forkhead Nutrition asmediatorofoxidativestressatthemetabolic Figure 4 ETC: electrontransportchain). chemoattractant protein-1,TLR4:Toll-like receptor4, impact onnutrientutilization postprandially( oxidative statusthatmaypossibly haveanunfavorable suggesting thatobesityis accompanied byanaltered tissue ofobesepatientscompared withleancontrols, expression wasfoundtobe higherinthewhiteadipose NOS (iNOS)areabundantinadipocytesandtheir to ROSgeneration.EndothelialNOS(eNOS)andinducible Additionally, NOSappearstobeasignificant contributor of non-mitochondrialsources ofROSinadipocytes( stimulated ROSgenerationunderlyingtheimportance in 3T3-L1adipocytesinhibitspalmitate-andglucose- such asglucoseorpalmitate( in fatcellsexposedtoexcessnutrientderivatives, of the enzyme expressed in adipocytes and is increased oxidase. NADPHoxidase4(NOX4)isthemajorisoform promote ROSproductioninadipocytes,suchasNADPH substrate overload( cells, ROS may derive from mitochondria and ETC adipocytes arenotconsideredpureenergy-producing sources ofintracellularROS inadipocytes.First,although players inadiposetissuefunction( to themetabolicbalanceofhumanbody( role intheinsulin-mediatedglucoseuptake,contributing multiple metabolicandhormonalactionswithacentral Adipose tissueisasanactiveendocrineorganwith Adipose tissue Nutrition andoxidativestress Oxidative metabolismandROSproductionaremajor 70 ). Inaddition,variousenzymescan Downloaded fromBioscientifica.com at09/26/202101:56:54AM 71 69 ). SilencingofNOX4 ). Therearedifferent 176 www.eje-online.org :2 68 73 ).

). R83

72 via freeaccess ). ). European Journal of Endocrinology www.eje-online.org three different groups of normal-weight, overweight and three differentgroupsofnormal-weight,overweight al et tissue ( signalinginvisceraladipose activation ofinflammatory fed withhigh-fatmealdisplayedanacutepostprandial first shown in a rat model by Magne response takesplaceintheadiposetissue( in adiposetissue( redox status that couldinterfere intheroleof free radicals oxidative stresscouldpossibly leadtoanadverselocal tissue ofobesemice( intheadipose of antioxidativeenzymeswas observed expression ofNADPHoxidaseanddecreased increased ROSproductionaccompaniedbyaugmented by Furokawa led toadysregulatedsecretionofadipokines,asshown stress, viaNADPHoxidaseactivation,andoxidativestress adipocytes, elevated FFA resulted in increased oxidative postprandially intheadiposetissue.Incultured and secretionofvariouscytokines( promotes macrophageaccumulationintheadiposetissue mediated viatheToll-like receptor(TLR-4),whichfurther The effectsofFFAs pathwaysare oninflammatory in adiposetissuethroughthereleaseofexcessiveFFAs. ingestion, ahigh-fatdietmayinducelocalinflammation pathwaysbynutrient direct activationofinflammatory and thequantityoffatconsumed( adipose tissue inflammation, independent of the quality metabolic syndromeexhibitanexacerbatedpostprandial a studybyMeneses tissue compared with a saturated fat diet ( responsein adipose attenuated postprandial inflammatory consumption ofadiethighinmonounsaturatedfatledto metabolic syndrome demonstrated that long-term On onehand,theLIPGENEstudyof75subjectswith different scientificgroups,butdataremaincontradictory. responseinadiposetissuewasaddressedby inflammatory fatalterspostprandial quality andquantityofdietary of adiposity( detected withinadiposetissue,independentofthedegree obese subjects, a similar increase in IL-6 and MCP-1 was promotes lipidsynthesisandinhibitslipolysis( of GLUTtransportersandglucoseuptake,additionally insulin-signaling cascade,asitenhancestranslocation adipocytes ( have highlightedthat insulin may elicit H physiological roleinitsmetabolicfunction.Earlyreports Review Finally, oxidativestresscanalsobe detected Following consumption of a meal, an inflammatory ROS inadiposetissueseemtohaveapotential ., 6 78

h aftertheconsumptionofamixedmealby ). Similarly, in humans as shown by Travers 74 ). ThistransientH t al et 79 ). Furthermore,whetherthespecific 84 ., What’s more,inthesamestudy, ). 83 t al et ). Therefore,thenutrition-induced . showedthatindividualswith 2 and others E Diamanti-Kandarakis O 2 82 productionamplifies 81 ). ). Apartfromthe t al et 2 O 2 production in 77 ., where rats 80 ). Thiswas ), whereas 75 , 76 ).

disrupt skeletalmuscleinsulin signalingandpromote insulin-signaling interference ( leading tofurtherexacerbation ofoxidativestressand pathway, increasingDAGsynthesisviaPKC activation pathway, AGEs formation, hexosamine biosynthesis through multiplemetabolicpathways,includingpolyol inhibition istheaugmentedfluxofglucosemetabolites dehydrogenase (GADPH)( sensitive glycolyticenzymeglyceraldehyde3-phosphate This excessROSpromotestheinhibitionofredox- increased superoxideformationandoxidativestress( Krebs cycle andETC capacity, ultimately leading to glycolytic fluxandglucoseoxidation,whichoverwhelms ofglucoseresultsinaugmented muscle. Increasedentry glucose andFFAs, accumulateintracellularlyinskeletal ample concentrationsofenergysubstrates,suchas as aconsequenceofhigh-fatmeal,oroverfeeding, to switch fromlipidtocarbohydrate use (‘metabolic conditions isknownasmetabolicflexibility. Inability uptake, oxidation and storageunder insulin-stimulated suppression oflipidoxidationandincreasedglucose of fattyaciduptakerduringfastingconditionstothe from predominantlylipidoxidationandhighrates availability. Thecapacityofskeletalmuscletoswitch pathways, asfuelutilizationshouldbeadjustedto ( uptake inskeletalmuscleviaGLUT4transporters energy homeostasis. roleinis fullofmitochondriathatexertaregulatory ( and representsacardinalsource ofenergyproduction of postprandial insulin-stimulated glucose disposal of the metabolic circulation. It accounts for about 80% Skeletal musclecanbecharacterizedasatrafficcontroller Skeletal muscle flexibility tolipidandinduceinsulinresistance( muscle mitochondrialabnormalitiesinfluencemetabolic literature dataarecontradictory, itwasproposedthat flexibility ismitochondrialoxidativecapacity. Although ( tissue forlipidstorageandthestatusofphysicalactivity availability, plasmaFFA levels, the availabilityofadipose metabolic flexibilityofanorganism,includingnutrient insulin resistance( associated withintramyocellularlipidaccumulationand inobesepatientsandisinflexibility’) wasobserved Nutrition andoxidativestress 86 88 85 ). Thisisacriticalstepinthebody’s metabolic ). Another factor that may be implicated in metabolic ). Asapureenergy-producingorgan,skeletalmuscle Simultaneously, increasedplasmaFFA levels also When calorieintakeexceedsenergyexpenditure, After nutrientintake,insulinpromotesglucose 87 ). Various factorsdeterminethe Downloaded fromBioscientifica.com at09/26/202101:56:54AM 89 ). TheresultofGADPH 90 ). 176 :2 88 R84 ). 48 via freeaccess ). European Journal of Endocrinology levels intheliverpromote effect inlivermetabolism. IncreasedmalonylCoA intracellular lipidaccumulation thathaveadetrimental fatintake leadtoincreasedFFAdietary liver supplyand In a similar setting with skeletal muscle, overfeeding or Liver enzymes ( oxidative phosphorylation muscle ( further exacerbatethemetabolicdysfunctionofskeletal cycle isinitiatedasthesemitochondrialabnormalities and increasedROSformation.Asaresult,vicious synthesis, impairedmitochondrialgeneexpression mitochondrial dysfunction,withdecreasedATP fatseemstopromoteoverfeeding andincreaseddietary PGC-1 encoding forthemitochondrialbiogenesisregulators daysshoweddownregulationofgenes fat dietfor3 In anotherstudy, volunteersfedanisoenergetichigh- itself suppressesmitochondrialATP production( muscle biopsies,fattyacidmetabolitepalmitoylcarnitine healthy volunteers’mitochondriaisolatedfromskeletal on mitochondrialbiologyandfunction( processes inskeletalmusclethroughdirectalterations mediators ( subsequent systemic release of FFAs and inflammatory causesROSproduction,with protein foldingmachinery proteins. IfUPRisprolonged,thepersistentoxidative protein foldinganddegradationofaberrantlypackaged protein response’(UPR),responsibleforERbiogenesis, ER stress, misfolded proteins activate the ‘unfolded associated with endoplasmic reticulum (ER) stress. During ( tyrosine phosphorylation activation, which in turn inhibit insulin receptor the inhibitorof complex activation, which results in degradation of c-Jun NH( toll-like receptor (TLR-4) in skeletal muscle promoting pathways,saturatedfattyacidsactivate inflammatory pathways ( turn impairsignalingofinsulin-stimulatedintracellular lipid metabolitesareactivesignalingmolecules,whichin (DAG), triacylglycerol(TAG) andceramides( mainly as long-chain fatty acyl-CoA, diacylglycerol storage leadstoectopicfataccumulationinskeletalmuscle, with limitedadiposetissueabilityforfatuptakeand insulin resistance( Review Dietary habits can also affect physiological metabolicDietary α and-1 Fig. 5 2 93 97 )-terminal kinase(JNK)andI , , ). 94 98 β andforgenesencodingmitochondrial , κ ). 95 B (I 91 ). Furthermore,FFAs directly activate ). Excessfatintakeinconjunction κ Ba) andnuclearfactor- 96 de novo ). Finally, lipotoxicityisalso and others E Diamanti-Kandarakis fattyacidsynthesis κ 101 99 b kinase(IKK) ). Innormal ). Overall, 92 κ B (NF ). These 100

κ B) ). ). NO, MDA and PAI-1 ( levels ofoxidativeandprothromboticmarkers,suchas FFA-exposed cultured hepatocytes displayed increased ceramides ( pathways, leading to formation of TAG, DAG and mitochondria andaredivertedtootherbiosynthetic activity. Asaresult,fattyacidscannotbeoxidizedin and inhibitcarnitinepalmitoyltransferase-1(CPT-1) function, aspancreatic protein misfoldingandERstress,whichcanpromote heavy anabolicburdenthatconsequentlypromotes and massivesubstratesupplytoliverexposesERa addition, inanexperimentalmodelbySoardo insulin signaling,includingPKCandJNKpathways.In cascadesthatderegulate initiate variousinflammatory resistance ( hepatic insulinresistancemayprecedesystemic visceral orskeletalmusclefatcontent,suggestingthat lipid accumulationwithoutanysignificantincreasein 3-day high-fat feeding led to athree-fold increase of liver insulin mRNAandimpairment ofinsulinsignaling FFA levels ledtoadecreaseininsulingeneactivityand cells, exposuretohighconcentrations ofglucoseand cell function( in diabeticpatientshasdetrimentaleffectspancreatic in pancreaticcellsandaltersinsulinsecretion( through theabovementionedmechanisms,actsdirectly levels, chronicinflammationandinsulinresistance oxidative stress,inducedbyelevatedglucoseandFFA more sensitivetoROSadverseactions( levels (SOD,catalaseandglutathioneperoxidase) by Tiedge in mitochondriaandcytosol( decreased insulinmRNA,ATP andcalciumfluxreductions production ofp21cyclin-dependentkinaseinhibitorand β to oxidativestress.InanexperimentbyMaechier Oxidative stress can significantly compromise Pancreatic HDL-cholesterol clearance( VLDL triglyceridesecretioncombinedwithelevated and dyslipidemiacharacterizedbyelevatedhepatic mediated suppressionofhepaticglucoseproduction lipid accumulationresultsinimpairedinsulin- persistently activated( signalingactivationif ROS productionandinflammatory Nutrition andoxidativestress -cells exposedtohydrogenperoxideactivated the Chronic elevationofplasmaglucoseandFFA levels et al β 103 102 -cells ., 108 ). As we mentioned above, these lipids ). In a rat model by Samuel β -cells arelowerinantioxidantenzyme ). Inculturedcellsofislets orHIT 104 β 102 Downloaded fromBioscientifica.com at09/26/202101:56:54AM -cells areinnatelymoresensitive ). Simultaneously, overfeeding ). Finally, intrahepatocellular 105 106 ). ). Furthermore,asshown 176 www.eje-online.org :2 107 ). Therefore, t al et 6 ). ., only t al et R85 et al β -cell via freeaccess ., ., .,

European Journal of Endocrinology www.eje-online.org which furtherdeteriorate chronic low-gradeinflammation andAGEproduction, that furtherexacerbateoxidative stress( which inturnactivatesmultiple metabolicpathways β intracellular mitochondrialROSformationinpancreatic addition, hyperglycemia by itself can trigger increased the underlyingmechanismsofthesederangements. In stress andaberrantfreeradicalgenerationcanbeone of the glucose-stimulatedinsulinsecretion( disorders (redarrowup). accumulation andsubsequentlytoincreasedmetabolic antioxidant capacityleadingtoincreasedfat decreased estrogens;squareinred: dysfunction andmetabolicdisorders;redarrowdown: accumulation, insulinresistance,peroxidation,B-cell down: decreasedoxidativestressleadingtofat increased antioxidantcapacitythroughER green arrowup:increasedestrogenicactivity, greensquare: disorders inwomen.+ER Nutrition asamediatorofoxidativestressinmetabolic Figure 5 -cells, promotingalocaloxidativemicroenvironment, Review α : presenceofEstrogenreceptors- β -cell function( and others E Diamanti-Kandarakis α ; Greenarrow 108 110 109

). ), including ). Oxidative

α ); ); sex hormonesandtheirimbalancehasbeenclearly mediators of oxidative stress in women, the role of diabetes mellitus( obesity, insulinresistance,metabolicsyndromeand rise tomultiplemetabolicdisordersinwomen,including is emerging asone of the principalparametersthatgive oxidative stress.Thenutrition-inducedstress stimulate multipleintracellularpathwaysandpropagate saturatedfattyacidsandglycotoxins well asdietary hypernutrition, high-fat,high-carbohydratemeals,as intracellular events in the major metabolic organs.Chronic Nutrition and calorieintake initiates aplethoraof metabolic disorders inwomen Nutrition asamediatorofoxidativestress in reproductive disorders stress infemalemetabolicand Nutrition asamediatorofoxidative antioxidant response( ROS formation,activates PCG1aandinducesan and mitochondrialbiogenesis, altersmitochondrial and mitochondrialreceptors promotesATP production oxidative stress( expenditure indirectly via mitochondrialfunctionand sensitive tissues,E2canregulatemetabolismandenergy β byprotectingand secretionenhancingisletsurvival and enhancelipidhomeostasis,insulinbiosynthesis Estrogen receptorsarealsopresentin pancreatic well asfailuretosuppressliverglucoseproduction( high-fat dietdisplayeddecreasedinsulinsensitivity, as In addition, liver-specific ER fat accumulationandactivationofstresskinases( metabolism was downregulated, inducing intracellular ( effect ininsulinsignalingandGLUT4expression muscle, estradiol(E2)receptor glucose homeostasis( pancreatic sensitive organs,includingskeletalmuscle,liverand not onlyinreproductivetissues,butalsoinsulin- metabolic function ( effects, theyareimportantregulatorsofbody’s to oxidativestress.Beyondtheirpurereproductive glucose homeostasis( demonstrated by their impact on insulin signaling and Nutrition andoxidativestress 114 -cell fromoxidativestressandapoptosis( In thepathogenesisofmetabolicdisordersand Apart fromthedirectactionsofestrogensoninsulin- Estrogens andtheirmetaboliteshavebeenlinked ). Inskeletalmuscleofovariectomizedmice,lipid β -cells, playing a modulatory roleininsulin– -cells, playingamodulatory 118 Fig. 5 ). Specifically, E2bindingtonuclear 111 112 119 ). Downloaded fromBioscientifica.com at09/26/202101:56:54AM 113 ). ). Their receptors are present , ). Analytically, inskeletal 120 α -knockout micefedwitha , 121 α (ER 176 ). Consequently, E2 α :2 ) hasapositive

117 ).

β R86 116 115 -cells via freeaccess ). ). ). European Journal of Endocrinology change intheirreproductive potential,directlyoriginating stress inmetabolicdysfunction. conclusions abouttherole of nutrition-relatedoxidative an importantconfoundingfactorindrawingdefinite metabolic derangements and can be established as clearly protectpremenopausalwomenfromdeveloping the metabolicandantioxidantpropertiesofestrogens of high-fatdiet( liver steatosisandinsulinresistanceafterconsumption mouse model, males had a higher propensity to developing and oxidativestressinadiposetissue( adiponectin andreductionsinimmunecellinfiltration more glucosetolerant,duetoincreasedexpression of weight-matched malemice.However, theyremained adiposity andenlargedadipocytesizecomparedwith obese maleandfemalemice.Femalesdisplayedgreater et al Furthermore, inanexperimentalmodelbyNickelson a lipid load inthe form ofheavy whipping cream ( with regardtoMDAandH as womenexperiencedloweroxidativestressthanmen, ( women displaysignificantlylowerlevelsofoxidativestress in comparisontohealthyyoungmen,premenopausal induced metabolicandoxidativederangements.First, focusing on gender-dependentdifferences in nutrition- oxidative balance. This is nicelydepicted in experiments abundance seem tofavorablyinfluencemetabolismand between noandrogensandexcessof( control butalsohowimportantistheroleofbalance androgen receptorsmayexertaprotectiveeffectinmetabolic after 8-weekhigh-fatdiet,highlightingthatnotonly fat, decreasedinsulinsensitivityandmarkeddyslipidemia knockout micedisplayedincreasedbodyweightand recent experimentalmodel,femaleandrogenreceptor- failure anddiabetesmellitus( and weresubsequentlypredisposedtopancreatic androgen excessexperiencedsystemicoxidativestress addition, inamousemodelbyLiu action and promote insulin resistance ( was shownthatandrogenexcess hyperandrorgenemia ispresent.InwomenwithPCOS,it syndrome(PCOS),where from womenwithpolycysticovary remains unclear. Themajorityofavailabledataoriginate human body. is highlightedasanatural,innateantioxidantagentof 127 Review During reproductiveage,hormonalstatusandE2 Regarding androgens,theirmetabolicroleinfemales Entering menopause,women experienceasevere ., high-fatdietwasadministeredtoweight-matched ). Analogousfindingswerereportedpostprandially, 130 ). Taken alltheaboveintoaccount, 2 O 125 2 levels,afteringestionof and others E Diamanti-Kandarakis per se ). However, inamore et al can impair insulin canimpairinsulin ., female mice with ., femalemicewith 122 129 , ). Inasimilar 123 126 , 124 ). β 128 ). In ). In -cell -cell

).

of estrogendeficiency( from estrogen–androgenimbalancewithmajordefect ( acting asregulatorsofkeyantioxidantgeneexpression able topreventandcounteractsuchmodificationsby Simultaneously, hormonereplacementtherapyis DNA repairabilityandtotalantioxidantstatus( reduced PON1Aactivityandelevatedlipoperoxidation, even duringperimenopausalperiod,manifestedby ( body, mainlythroughadecreaseinantioxidantdefenses been showntoincreaselevelsofoxidativestressinthe cardiovascular events( resistance andmetabolicsyndrome,aswelladverse central adiposity, dyslipidemia,progression of insulin an abruptreductioninmetabolicrate,shifttoincreased signs. Lossoftheirmaincirculating estrogen,E2leadsto many tissuesandproducesavarietyofsymptoms replacement therapy(HRT) usecompared with control was reducedby62%inwomen withcurrenthormone population-based prospective cohortstudy, diabetesrisk insulin resistanceandmetabolic dysfunction.Ina also underlinedtheprotectiveeffectofestrogenagainst replacement therapy( comparison toovariectomizedmicereceivinghormone glucose tolerance and whole-body insulin resistance in mass, reducedwhole-bodyenergyexpenditure,impaired ovariectomized miceledtoincreasedbodyweightandfat Camporez improved thesederangements( resistance. Administration of soyisoflavones significantly oxidant markers,aswellglucoseintoleranceandinsulin blood antioxidantswithaconcomitant elevation of with high-fatdietshowedamarkedreductionofwhole in anotherexperimentalmodel,ovariectomizedratsfed females supplementedwithestradiol( in comparison with intact females or ovariectomized sucrose dietdisplayedhighersusceptibilitytoperoxidation, Busserolles metabolic imbalancewasalsoevaluated.Inastudyby background. Thepotentcontributionofnutritiontothis and estrogenreplacementwereusedtomimichormonal evaluated inanimalmodels,whereartificialmenopause oxidative dysfunctionduringmenopausewasextensively postmenopausal women( metabolic andendothelialdysfunctionthatcharacterizes characterizes postmenopausal women potentiates the Nutrition andoxidativestress 135 133 In addition,themarked reduction in estrogen has The unique role of estrogen deficiency in metabolic and , ). Women experienceincreasedoxidativestress 136 ). Consequently, thispro-oxidantstatethat et al et al . demonstratedthat4-weekhigh-fatdietin ., ovariectomizedfemaleratsfedwithhigh- 132 140 131 Downloaded fromBioscientifica.com at09/26/202101:56:54AM 132 ). ). Largeclinicalstudieshave ). Ovariansenescenceaffects , 137 ). 176 139 138 www.eje-online.org :2 ). Analogously, ). Furthermore, R87 134 via freeaccess ). European Journal of Endocrinology www.eje-online.org during embryonic development and implantation( during embryonic ( especially whenantioxidantdefensesareinsufficient spindle andincreasedriskforabnormalzygoteformation, oxidative stress before fertilization leads to disrupted meiotic protein(StAR)( regulatory mainly throughalteredproductionofsteroidogenicacute impaired cholesterol utilization andproteinsynthesis, women undergoing assisted reproductive techniques oxidative stressinfertility. Themajorityoftheminvolve conducted so farinorder to explore theputative role of in ordertosecurenormalovum functionanddevelopment. ofadelicateoxidative balance arecrucial and preservation oxidative equilibriumintheovarianmicroenvironment responseattheimplantation site ( secretory of cyclic GMP, which mediates estrogen-stimulated uterine contribute asananti-plateletagent,wellaregulator Although its function is not established, NO seems to overexposedtoH it hasbeenshownthatovary of femalereproductivesystem.Inovariansteroidogenesis, oxidative metabolismisalsoimplicatedinotherfunctions protein ATP production ( and antisteroidogenicactions,DNAdamageinhibited meiosis IIprogression,leadingtodiminishedgonadotropin evolution, whereasontheotherhand,ROSadverselyaffect follicleisanimportantpromoteroftheovulatory ovulatory suggesting thatcontrolledROSproductionbythepre- by anincreaseinROSandinhibitedantioxidants, follicleisinduced resumption ofmeiosisIaprimary maturation, asseenin environment duringdifferentstagesofphysiologicaloocyte play acomplexandmultifunctionalroleintheovarian of folliculogenesis.Freeradicalsandantioxidantsseemto Oxidative metabolismisacriticalintraovarianregulator reproductive disorders Nutrition asamediatorofoxidativestress infemale metabolic state. as hormonalfluctuationscanuniquelydetermineher woman isadecisivedenominatorinthisco-interaction, estrogens/with orwithoutandrogenexcess,ofevery However, thehormonalbackground,withorwithout development ofvariousmetabolicdisordersinwomen. oxidative stresscansignificantlycontributetothe sensitivity ( women with preexisting diabetes and increased insulin individuals ( 144 Review Consequently, a plethoraofstudieshavebeen Concluding, calorieintakeanditssubsequent ). Finally, role acritical,regulatory NOseemtocarry 142 141 ). ). HRTalsoimprovedglucosecontrolin Fig. 6 143 143 ). Apart from folliculogenesis, ). Apart from folliculogenesis, . For example, on one hand, . Forexample,ononehand, ). In addition, exposure to ). Inaddition,exposureto and others E Diamanti-Kandarakis 146 2 ). Overall, ). Overall, O 2 led to ledto 145

). ). potentially impairfertility, byalteringfollicularphysiology and itwasshownthatelevatedFFA concentrationscan cultured model by Valckx investigated, buttoamuchlesserextent.Inanexperimental local oxidativestressintheovarianmilieuhasalsobeen achieving pregnancyinthesewomen( plasma antioxidantstatuswasshowntobebeneficialin with successrates( (TAC) ofpatientsundergoingIVFwaspositivelyassociated other hand, follicular fluid total antioxidant capacity fertilization andpregnancyrates( quality,lower ovarianresponse,poorerembryo decreased fluid ofwomenundergoingARTwereassociatedwith MDA, ROS,NOandlipidperoxidation(LPO)infollicular pregnancy outcomes.Specifically, increasedlevelsof of oxidativestresswerecorrelatedwithfertilizationand (ART), wherevarioussystemicandfollicularfluidmarkers significantly correlatedwithconceptionrates( IVF, follicularfluidlevelsofsoluble form ofRAGE(sRAGE) outcomes ( levels werethemostsignificantpredictorsofpregnancy development. What’s more,lowerfollicularfluidAGE follicular growth,fertilizationratesandembryonic follicular fluidAGElevelsnegativelycorrelatedwith undergoing IVF, have documented that serum and ( potential roleofAGE-RAGEsysteminfemaleinfertility Recently, differentresearch groupshaveinvestigatedthe dysfunction( microenvironment andovulatory tissue, promotingsignificantperturbationsinovarian contributes toincreasedAGEdepositioninovarian inactivity withoxidative biomarkers in follicular fluid ( relationship betweentotalcalorieintake,BMIandphysical ( development and negativelyinfluenceembryonic rich diet can induce oxidative stress in oocyte environment undergoing assistedreproductionprogramrevealedthatfat- Analogously, study of 236 women an observational and reducingoocytedevelopmentalcompetence( delicate, marginal threshold distinguishing beneficial and in femalereproductive physiology ( can potentiallyleadtoinfertility. parameter in theinitiation of ovarian dysfunction, which Overall, intraovarianAGEaccumulationcanbeadecisive ( AMH, awell-knownmarkerofovarianreserve Finally, sRAGE seems to be positively correlated with Nutrition andoxidativestress 154 157 Finally, AGEconsumption increaseddietary The role of nutrition and its impact on inducing The roleofnutritionanditsimpactoninducing Concluding, oxidativemetabolism hasauniquerole ). However, Kazemi ). Jinno in vitro 158 t al et inthepresenceofFFAs untiltheantralstage ). Inanotherstudyofwomenundergoing et al ., in a retrospective analysis of women 150 ., early secondary murine follicles were murine follicles were ., early secondary , Downloaded fromBioscientifica.com at09/26/202101:56:54AM t al et 151 . failed to prove a potential . failedtoproveapotential ), whereasenhancedblood 147 176 , i. 6 Fig. 152 148 :2 ). , ). Thereisa 149 ). Onthe R88 160 159 156 155 153 via freeaccess ). ). ). ). ). European Journal of Endocrinology ovary syndrome). Reactive oxygenspecies,NO:nitricoxide,PCOS:polycystic manifestation ofvariousreproductivedisorders.(ROS: augment detrimentaleffects ofpro-oxidantsandmediatethe alters femalereproduction.Nutritionaloxidativestresscan between pro-oxidantsaffects intraovarianenvironmentand regulator infemalereproductivedisorders.Dysequilibrium Nutritional oxidativestress:animportantintraovarian Figure 6 depletion ofovarianfollicles andreducedabilityto far extensively characterized in terms of gradual Ovarian functionaldecline withaginghasbeenso Ovarian aging therapeutic target,arelimited. oxidative stressinfemalereproductivedysfunction,as a solid conclusionsabouttheroleofnutrition-promoted reproductive abnormalities( could beapotent,underlyingmechanismofvarious normal ovarianfunction.Therefore,oxidativestress tosecure pro-oxidant:antioxidant ratioismandatory harmful effects of oxidative stress and tightly controlled Review 5 ). However, dataestablishing and others E Diamanti-Kandarakis

levels decline( by excessiveROSgenerationcombinedwithantioxidant aging originatesfromacontinuousimbalance,derived development ( produce oocytes competent for fertilization and further observed in different ovarian compartments, including indifferentovariancompartments,including observed in oxidativelydamagedlipids,proteinsandDNAare mouse modelbyLim catalase downregulation( superoxide dismutase,Mndismutaseand also occurs in granulosa cells,accompanied by Cu/Zn With theweakeningofantioxidantdefense,aging of freeradicals,arereducedinoocyteswithage( glutathione transferase,whichareeffectiveintheremoval in premenopausalwomen( found to be higher in postmenopausal women than lipoproteins (ox-LDL),4-hydroxynenalandMDAwere cytokines andpro-oxidantbiomarkerssuchasoxidized in the ovary havenotbeenadequatelyevaluatedand in theovary the direct effects of nutrition-induced oxidative stress follicle shouldbeencouraged. Theroleofnutritionand mitochondrial dysfunction andROSoverloadinthe and furtherinvestigation of thenetworkinvolving oxidative stressinovarianagingareonlyindicatory found tobedecreasedinagedovariesofmice( powerful enzymaticsystemofAGEscavenging,wasalso the activityandexpressionofglyoxalase-1(GLO1), a and ultimatelytriggerovariandysfunction( of oxidative stress response through RAGE interaction, compromised efficiencyofvascularizationandactivation initiate adversemolecularintraovarianevents,such as across lifespanmay of thesecompoundsintheovary aging ( suggest apossiblecorrelationofAGEswithovarian follicles of premenopausal women,findingsthat andatretic intheprimordial,primary were observed cells ( in granulosathecainterna,endothelialandstromal beingpresent RAGE washighlyexpressedintheovary tissue obtainedfromreproductive-agedwomen,whereas demonstrated thatAGEsarepresentinnormalovarian the processof ovarian aging.A study by our group increase levelsofoxidativestressinthebody( as themarkedreductioninestrogen,havebeenshownto hormonal alterationsthataccompanyovarianaging,such alterations ofantioxidantenzymeexpression( granulosa cellsandovarianinterstitialtissue,alongwith Nutrition andoxidativestress Analytically, serum concentrations of inflammatory Overall, experimentaldataregardingtheroleof Furthermore, AGEsmayalsobeinvolvedin 168 169 ). Inaddition,increasedlevelsofpentosidine ). Consequently, potential accumulation 162 161 ). ). Oxidativestress-inducedovarian et al Downloaded fromBioscientifica.com at09/26/202101:56:54AM ., significant age-related increases ., significantage-relatedincreases 165 163 ). Similarly, asshownbya ). In contrast, GSH and ). Incontrast,GSHand 176 www.eje-online.org :2 170 166 167 171 ). Finally, ). Finally, ). ). R89 164 via freeaccess ). ). European Journal of Endocrinology www.eje-online.org PCOS ( has alsobeenhighlightedas anotherpotentmodulatorof net ofthesyndrome( environmental parameters,are allinvolvedintheinterplay conjunction withthepivotal contributionofgeneticand insulin resistanceandlow-gradeinflammation, in alterations,androgen excess, gonadotropin-secretory etiopathophysiological coreremainsvague;however, clinicalpractice ( encountered ineveryday common endocrinopathiesofpremenopausalwomen, syndrome(PCOS)is one ofthemost Polycystic ovary Polycystic ovarysyndrome stress infemaleinfertility. to investigatedeeperthefieldofdiet-inducedoxidative inorder examinations cantakeplace,aremandatory and biologicalsample interventions in which dietary future, prospective,well-designedpregnancystudies, of womenwithoutovarianstimulation.Therefore, hormones, creatingamilieuthatdiffersfromtheFF follicle maturationisstimulatedwithexogenous fluid compositioninwomenundergoingIVFwhere The majorityofthemhavefocusedonfollicular induced oxidativestressininfertilityarelimited. only withclomiphenecitrate( improve ovulationratesincomparisontowomentreated induction in women withunexplainedinfertility failed to was administratedwithclomiphenecitrateforovulation N and Polak idiopathic infertilitywerealsoreportedbyWang levels ofROSintheperitonealfluidwomenwith compared withfertilecontrols( peritoneal fluid of women with idiopathic infertility significantly contributestoitspathogenesis. remains unclear, it is believed that oxidative stress anovulation andspermdefects( known causesofinfertility, includingbutnotlimitedto tests have been performed on both partners to rule out oftimed,unprotected intercourse where after 12 months exclusion and is defined as the inability toconceive Idiopathic (unexplained) infertility is diagnosed by Unexplained infertility to reachmoredefiniteconclusions. warrant more experimental and clinical models, in order -acetyl cysteine(NAC),apotentantioxidantcompound, Review Human studiesregardingtheroleofnutrition- Total antioxidantstatuswasfoundtobelowerin 178 , t al et 179 . ( ). 172 , 176 173 , 177 ). However, astudyinwhich ). Recently, oxidative stress 174 5 and others E Diamanti-Kandarakis 172 ). Althoughitsetiology ). ), whereaselevated 175 ). Its t al et

. postprandial hyperglycemia,hasalsobeenstudied with PCOS( dismutase (SOD),whoseactivitywasenhancedinwomen activities were shown to be decreased, and superoxide such asparaoxonase-1(PON-1)andglutathione,whose detected intheconcentrationsofenzymaticantioxidants, PCOS ( free radicals,wasfoundtobedecreasedinwomenwith which represents the ability of human body to eliminate (TAC), an aggregative index of plasma antioxidant state, perpetuating oxidativestress.Total antioxidantcapacity theredoximbalanceand suffering fromPCOS,conserving levels ofantioxidantsalsoseemtobeaffectedinwomen to beelevatedinwomenwithPCOS( asymmetric dimethylarginine (ADMA) levels were shown Murri altered inPCOS.Specifically, inarecentmeta-analysisby accumulating datahighlight theroleofoxidativestress with PCOS, as well ( drive analogousdetrimental cellulareventsinwomen all thesepathophysiological processesandseemsto above, oxidative stress is a common denominator of and endothelialdysfunction( by obesity, abdominaladiposity, insulinresistance metabolic signaling, PCOS is commonly accompanied characterize womensufferingfromPCOS.Regarding both reproductive and metabolic dysfunctions that to oxidativestress,asstresscontributes to and metabolicabnormalitiescouldbeuniquelylinked glycemic dysregulationinwomenwithPCOS( impact onpancreatic hyperglycemia-induced inflammationhasanadverse sensitivity, it wasrecently shown by Malin with PCOS( markers even in lean women of various inflammatory and the concomitant upregulation of the expression to increasedsensitizationofleukocyteshyperglycemia predominates inPCOS,seemstosignificantlycontribute peroxidase (GPx)( action ofenzymaticantioxidants,suchasglutathione What’s more,hyperglycemiawasalsoshowntoalterthe and NF- markers (i.e., TNF-a stimulating secretion of inflammatory presence of obesity and abdominal adiposity, via in womensufferingfromPCOS,independentofthe monocytes in response to hyperglycemia was observed in PCOS.Specifically, increasedROSproductionby Nutrition andoxidativestress Nutrition-induced oxidativestress,through Various pro-oxidantbiomarkershavebeenshowntobe PCOS could serve asamodelinwhich reproductive PCOS couldserve et al. 181 κ B) andactivationofNADPHoxidase( , , homocysteine,malondialdehyde(MDA)and 182 180 188 ), whereasvariousabnormalitieswerealso , , 183 189 187 , β ). Interestingly, apartfrominsulin 184 ), andhyperandrogenemia,which -cell function,furtherexacerbating Downloaded fromBioscientifica.com at09/26/202101:56:54AM 48 ). ). Regarding reproduction, 176 176 ). Asdiscussed 180 :2 ). Conversely, 190 t al et 185 , , . that 191 R90 186 via freeaccess ). ). European Journal of Endocrinology t al. et linked toinsulinresistance. InamousemodelbyCai dysfunction, itiswellestablished thatAGEsareclosely dysfunction in PCOS ( in granulosacellswithpotential interferenceinovarian signaling pathways,specificallywithinsulin Accumulating AGEsinterfere with intracellularovarian as well as NF- endothelial ovariancellsandhigherexpressionofRAGE increased AGEdepositionintheca,granulosaand against glycation( ovarian glyoxalase-1activity, aprotective enzyme in thecaandgranulosacells,aswelldownregulated rats displayedincreaseddepositionofAGEsandRAGE women withPCOS.Specifically, female high-AGE-fed follicular maturationprocess( indicating thepotentialroleofoxidativestressin AGE levelsinPCOSwomen,afindinghumanstudies these women( effects in both reproductive and metabolic function of obesity and insulin resistance, exerting unfavorable women withPCOS,independentofthepresence diet. AGEs were shown to be distinctively elevated in produced endogenouslyaswellderivingmostlyfrom withdominantpro-oxidantcapacity,inflammatory studies inPCOSwomen.AGEsareknowntobeextremely menopause inwomenwithPCOS( from humanstudiesdonotseemtoconfirmanearly ( washup ofovarianreserve PCOS mayinduceaccelerationofagingprocessandearly ovarian agingprocess.Notsurprisingly, itisimpliedthat and follicularfluid,derangementsthatalsoprevailin oxidative stresswerefoundtobealteredbothinserum byRezvanfar ovary hyperandrogenism-induced murine model of polycystic ( and were accompanied by poorer fertilization rates displayed thehighestlevelsofROSingranulosacells ( IVF populations ofinfertilewomenwhounderwent markers ofoxidativestresswereassessedindifferent 193 qualityanddecreasedpregnancyrates( embryo lower ratesofoocytematurationandfertilization,poor capacity (TAC), whichweredirectlyassociatedwith ROS andMDA,aswelldecreasedtotalantioxidant with PCOSdisplayedincreasedfollicularfluidlevelsof inPCOS.Womenin themicroenvironmentofovary 194 194 Review ). Infact,inastudybyKaruputhula AGEs haveadirectimpactontheovariancellsof Equally significantarethedataonAGEs,derivedfrom ). Finally, weshouldmentionarecentstudyof ). Amongthewholecohort,womenwithPCOS , itwasdemonstratedthat micefedwithahigh- κ 198 B p65subunit in granulosa cells ( ). Also,AMHcorrelatesstronglywith 200 t al. et , , inwhichvariousmarkersof 201 202 195 199 ). PCOovariesdisplayed ). Concerningmetabolic ). However, clinicaldata and others E Diamanti-Kandarakis ). 196 , 197 t al et ). ., various 146 , 168 192

). ). , glutathione reductase(GR), vitamins A,C,E,copper, zinc cadmium andreducedlevels ofTAC, SOD,catalase, GPx, increased concentrationof ROS,NO,LPO,iron,lead, those withthedisease( reported increasedlevelsof oxidativestressmarkersin circulation ofpatientswithendometriosis,othershave increased oxidative stress in the peritoneal fluid or in bibliography. Althoughsomestudiesfailed toobserve stress inendometriosis.Dataaremainlycontradictory investigating theroleofnutrition-relatedoxidative abnormalities inwomenwithPCOS. process inreproductiveaswellmetabolic rest etiologicalparameters,orchestrates thepathogenetic evident thatoxidativestress,inconjunctionwiththe inordertosetsolidknowledge,itbecomes is mandatory oxidative statusandviceversa.Althoughmoreresearch insulin resistance,bothofwhichareaggravatorsthe PCOS, asthesewomendisplayhyperandrogenemiaand etiology ofmetabolicandreproductiveaberrationsin improvement oftheirmetabolicprofile( and oxidativestressmarkers,depictingasignificant parallel decreaseinserumAGE,insulinlevels,HOMA-IR AGEintakeinwomenwithPCOSresulteda dietary analogous human model by Tantalaki mice fedwithanisocaloricAGE-freediet( adiposity andeventuallydiabetes,incomparisonwith AGE dietdemonstratedinsulinresistance,abdominal extent ofcelldeath( antioxidant defensesaredecisiveindeterminingthe release andapoptosis.Cellularoxidantproperty turn activatesmultiplesignalingpathways,cytokine place, leadingtoexcessiveproductionofROSthatin toxic compounds,autoxidationofhemoglobintakes cavity. Asfreehemeandironareconsideredgenerally derivatives toendometrioticlesionsorperitoneal the pro-oxidanthemoglobintransfershemeandiron endometriosis, oneofwhichisoxidativestress( been postulated regarding the pathophysiology of been associatedwithinfertility. Various theorieshave affects 6–10% ofwomenreproductive age andhas tractoreveninlungs.Endometriosis viscera, urinary outside theuterus,mostofteninovaries,abdominal unknown etiology, inwhichendometrialtissueispresent Endometriosis is a benign gynecologic disorder of Endometriosis Nutrition andoxidativestress A plethoraofscientificstudieshavefocusedon After bleedingandhemolysisinendometriosis, Oxidative stress holdsa respectable share inthe 205 5 ). InarecentstudybySingh Downloaded fromBioscientifica.com at09/26/202101:56:54AM ). 176 www.eje-online.org :2 204 t al et ). 203 5 ., lower ). ). Inan R91 et al via freeaccess ., European Journal of Endocrinology www.eje-online.org acids orpolyunsaturatedfatty acidsandpolyphenols, months,enrichedinmonounsaturated fatty diet for3 Ceriello in healthyindividuals( and bodycoretemperature (twomarkersoflongevity) stress anddecreasedsignificantlyfastinginsulinlevels example, 6-monthcaloricrestrictionattenuatedoxidative oxidative balance and promoting cell longevity. For patterns canexerttheexactlyoppositeeffect,securing to ovariandysfunction( protective enzymeagainstglycation,ultimatelyleading the cellularmilieuanddownregulatingglyoxalase-1, a altering AGEs andRAGEinovariantissueswasobserved, in femalehigh-AGE-fedmice,increaseddeposition of ( can potentiallyleadtotissueinjury actionsofAGEsthat depicted thepotentinflammatory increase inserumTNF-a,CRPandVCAM-1levels fed for6 weeks indiabeticpatientsresultedasignificant variety ofdiseases. status,which,inturn,canpredisposetoa inflammatory are repeated,theyimposeasustainedoxidativeand physiological functions. When these derangements an acutesettingcanmodifyintracellularandextracellular milieuin Nutrition-induced oxidativeandinflammatory oxidative homeostasis Long-term effects ofnutritionin possible linksandconclusions. not correlated with clinicaloutcomes, in order to reach were enhanced( and antioxidantmarkers,specificallySODGPx, and lipidhydroperoxides,weresignificantlyattenuated peripheral oxidative stress markers, including MDA diet wasadministeredinwomenwithendometriosis, a studybyMier-Cabrera endometriosis, incomparisonwithcontrols( redox systemweredetectedininfertilewomenwith vitamin Clevelsandimbalancedintrafollicularthiol- lower plasmaSODconcentration,follicularfluid in womensufferingfromendometriosis.Specifically, endogenous antioxidantcompoundsarealsodisrupted and VEGF),MCP-1ox-LDL( (IL-6, TNF-alphaandIL-beta),angiogenicfactors(IL-8 cytokines concentrations ofMDA,proinflammatory of thesepatientshasalsobeenfoundtocontainhigh undergoing IVF( inwomenwithendometriosis and seleniumwasobserved Review On theotherhand,restrictedcalorienutritional In astudybyVlassara et al ., diabeticpatientsfollowing aMediterranean 149 209 ). Analogously, theperitonealfluid ). However, datawere laboratory 200 210 et al et al , ). Inaddition,inastudyby 201 ., whenahigh-antioxidant ., inwhichhigh-AGEdiet ). and others E Diamanti-Kandarakis

19 206 ). Simultaneously, ). Furthermore, 207 , 208 ). In

stress modulatesandinterferesdirectlyindirectly milieu. Specifically inwomen,nutritional oxidative pathways ofvariousorgans,unfavorablyalterthecellular clustering ofmolecularchangesinthemainsignaling accompanying postprandialoxidativestressinitiatea oxidative stressinhumanbody. Nutrientintakeandits Nutrition constitutesoneofthemajormodulators Conclusion the occurrenceofvariousdiseasesinwomen. detrimental pathophysiologicalpathwaysandpromote divergences caneasilyviolatethiscellularbalance,initiate both inanacuteandachronicsetting.Nutritional catalytically inthemaintenanceofoxidativebalance controls ( improved basalendothelialfunction,incomparisonwith displayed increased plasma antioxidant capacity and References the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagencyin Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest into accountasarecurrentlyconsideredcontributors. the qualityandtimingofmealsshouldalsobetaken of foodquantityremainsthemostwell-studiedfactor, but disorders, modificationofnutritionalhabitsbyreduction Therefore, in women with metabolic and reproductive targeted therapeutic modalitiesachallenging field. pathophysiological linksarestillescaping,making are ultimatelycompromised.Nevertheless,theexact with themetabolicandreproductivefunctions,which Nutrition andoxidativestress 1 5 4 3 2

Agarwal A, Aponte-Mellado A, Premkumar BJ,Shaman A& Agarwal A, Dalle-Donne I, Rossi R,Colombo R, Giustarini D &Milzani A. Turrens JF. Mitochondrialformationofreactiveoxygen Halliwell B. Reactiveoxygenspeciesinlivingsystems:source, Commoner B, Townsend J &Pake GE.Freeradicalsinbiological Gupta S. Theeffectsofoxidativestress onfemalereproduction: 2006 Biomarkers ofoxidativedamageinhuman disease. jphysiol.2003.049478) species. Medicine biochemistry, androleinhumandisease. materials. Overall, itbecomesclearlyevidentthatnutritionacts 52 211 Journal ofPhysiology Journal 601–623. 1991 Nature ). 91 14S–22S. 1954 (doi:10.1373/clinchem.2005.061408) 174 Downloaded fromBioscientifica.com at09/26/202101:56:54AM (doi:10.1016/0002-9343(91)90279-7) 2003 689–691. 552 335–344. (doi:10.1038/174689a0) American Journal of American Journal 176 :2 (doi:10.1113/ Clinical Chemistry R92 via freeaccess

European Journal of Endocrinology

18 26 25 24 23 21 20 19 17 16 15 14 13 11 10 22 12 9 8 6 Review 7

Allen RG &Tresini M. Oxidative stressandgeneregulation. Finkel T. Reactiveoxygenspeciesandsignaltransduction. Burton GJ &Jauniaux E.Oxidativestress. Valko M, Leibfritz D,Moncol J, Cronin MT, Mazur M& Telser J. Sies H. Oxidativestress:oxidantsandantioxidants. of Pisoschi AM &Pop A.Theroleofantioxidantsinthechemistry Ott C, Jacobs K,Haucke E,NavarreteSantos A,Grune T&Simm A. Vlassara H, Cai W, Crandall J,Goldberg T, Oberstein R,Dardaine V, Ramasamy R, Yan SF &Schmidt AM.Advancedglycation Vlassara H &Palace MR.Diabetesandadvancedglycation Pacher P, Beckman JS&Liaudet L.Nitricoxideandperoxynitrite Forstermann U &Sessa WC.Nitricoxidesynthases:regulationand Rosselli M, Keller PJ&Dubey RK.Roleofnitricoxideinthe Davies KJ. Oxidativestress:theparadoxofaerobiclife. Droge W. Freeradicalsinthephysiologicalcontrolofcellfunction. Halliwell B &Cross CE.Oxygen-derivedspecies:theirrelationto O’Keefe JH &Bell DS.Postprandialhyperglycemia/hyperlipidemia Fisher-Wellman K &Bloomer RJ.Macronutrientspecific andpostprandial Sies H, Stahl W&SevanianA.Nutritional,dietary Halliwell B. Oxidativestress,nutritionandhealth.Experimental Tangvarasittichai S. Oxidativestress,insulinresistance,dyslipidemia S0891-5849(99)00242-7) Free RadicalBiologyand Medicine Life bpobgyn.2010.10.016) Clinical ObstetricsandGynaecology 2007 human disease. Free radicalsandantioxidantsinnormalphysiologicalfunctions Physiology 2015 oxidative stress:areview. Biology Role ofadvancedglycationendproductsincellularsignaling. 2002 glycotoxins,amajorriskfactorfordiabeticangiopathy.dietary mediatorsareinducedby Peppa M &Rayfield EJ.Inflammatory Amino Acids endproducts: fromprecursorstoRAGE:roundandwego. (doi:10.1046/j.1365-2796.2002.00932.x) endproducts. (doi:10.1152/physrev.00029.2006) in healthanddisease. (doi:10.1093/eurheartj/ehr304) function. Reproduction Update biology, physiologyandpathophysiologyofreproduction. Society Physiological Reviews ehp.94102s105) Perspectives human diseaseandenvironmentalstress. j.amjcard.2007.03.107) ofCardiology American Journal (postprandial dysmetabolism)isacardiovascularriskfactor. (doi:10.2174/157339909789804369) insulin resistance. postprandial oxidativestress:relevancetothedevelopmentof oxidative stress. Free RadicalResearch strategies foroptimizationofnutritionalantioxidantintakeinhumans. 456–480. and type2diabetesmellitus. (doi:10.1186/1477-7827-10-49) a review. 2001 39 97 99 Symposium 2014 44–84. 55–74. 15596–15601. Reproductive BiologyandEndocrinology 1997 52 (doi:10.4239/wjd.v6.i3.456) European Heart Journal European Heart 1994 2012 3–6. 2 Journal of Internal Medicine ofInternal Journal 411–429. 82 International Journal of Biochemistry andCellBiology ofBiochemistry Journal International (doi:10.1016/j.biocel.2006.07.001) (doi:10.1016/j.ejmech.2015.04.040) Journal ofNutrition Journal 102 1995 (doi:10.1080/15216540252774694) 291–295. 42 Current DiabetesReviews 1996 1998 2002 (Supplement10)5–12. 1151–1161. Physiological Reviews (doi:10.1073/pnas.242407999) 61 (doi:10.1016/j.redox.2013.12.016) 25 82 4 European Journal ofMedicinal Chemistry European Journal 1–31. 3–24. 57–74. 47–95. (doi:10.1113/expphysiol.1997.sp004024) World ofDiabetes Journal 2007 2000 2012 (doi:10.1042/bss0610001) (doi:10.1093/humupd/4.1.3) 2011 (doi:10.1007/s00726-010-0773-2) 2005 (doi:10.3109/10715769609145656) 100 (doi:10.1152/physrev.00018.2001) and others E Diamanti-Kandarakis 28 33 899–904. 25 2002 463–499. 829–837,837a–837d. 135 Best PracticeandResearch Environmental Health 2009 2007 287–299. (doi:10.1289/ 969–972. 251 2012 5 87 228–238. (doi:10.1016/ 87–101. Experimental Experimental (doi:10.1016/ 315–424. 10 (doi:10.1016/j. 2015 Biochemical 49.

IUBMB Human 6

Redox

PNAS

Nutrition andoxidativestress 30 29 28 27 43 42 41 40 34 33 32 39 38 36 35 31 37

Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA &Ganie SA. Finkel T &Holbrook NJ.Oxidants,oxidativestressandthebiology Maritim AC, Sanders RA&Watkins JB 3rd.Diabetes,oxidativestress, &Aggarwal BB. Reuter S, Gupta SC,Chaturvedi MM Li H, Horke S&Forstermann U.Vascular oxidativestress,nitric Fetoui H, Garoui M&Zeghal N.Protein restrictioninpregnant-and Saad MI, Abdelkhalek TM,Haiba MM,Saleh MM,Hanafi MY, Aiken CE, Tarry-Adkins JL, Penfold NC,Dearden L&Ozanne SE. Thompson LP &Al-Hasan Y. Impactofoxidativestressin Lee HS. Impactofmaternaldietontheepigenomeduringinutero Dandona P, Ghanim H,Chaudhuri A,Dhindsa S&Kim SS. Dandona P, Aljada A,Chaudhuri A,Mohanty P&Garg R.Metabolic Gamborg M, Byberg L,Rasmussen F, Andersen PK,Baker JL, Armitage JA, Taylor PD &Poston L.Experimentalmodelsof Barker DJ. Maternalnutrition,fetalanddiseaseinlaterlife. Barker DJ, Osmond C,Golding J,Kuh D&Wadsworth ME. Growth Barker DJ, Winter PD, Osmond C,Margetts B &Simmonds SJ. 1448–1454. diseases; amechanisticinsight. Oxidative stress,mitochondrialdysfunctionandneurodegenerative of ageing. Toxicology and antioxidants:areview. j.freeradbiomed.2010.09.006) Free RadicalBiologyandMedicine Oxidative stress,inflammation,andcancer:howaretheylinked? (doi:10.1016/j.atherosclerosis.2014.09.001) oxide andatherosclerosis. 2009 in theiroffspring. lactating rats-inducedoxidativestress andhypohomocysteinaemia 2015 programming inF1offspring. exacerbate perinataloxidativestressresultingindiabetogenic Tawfik SH &Kamel MA. Maternal obesityandmalnourishment 2015 offspring exposedtoanobesogenicmaternaldiet. biogenesis, andincreasedlipidperoxidationinfemalemouse dysregulationofmitochondrial Decreased ovarianreserve, (doi:10.1155/2012/582748) fetal programming. 634–645. from 20Nordicstudies. adulthood: meta-regressionanalysisofsex-andage-specificresults Birth weightandsystolicbloodpressureinadolescence emm.2010.42.4.033) Experimental andMolecularMedicine potential relevancetoatherosclerosisandinsulinresistance. stress: Macronutrient intakeinducesoxidativeandinflammatory between obesity, diabetes,andinflammation. syndrome: acomprehensiveperspectivebasedoninteractions 74 Bengtsson C, Canoy D,Droyvold W, Eriksson JG,Forsen T 3–8. energy richdietduringdevelopment. developmental programming:consequencesofexposuretoan Nutrition bmj.298.6673.564) from cardiovasculardisease. in utero,bloodpressurechildhoodandadultlife,mortality 1989 Weight ininfancyanddeathfromischaemicheartdisease. nu7115467) and adulthood. life andthedevelopmentalprogrammingofdiseasesinchildhood 101–110. (doi:10.1113/jphysiol.2004.079756) 93 39 30 2 577–580. 263–270. 643–655. 1548–1556. 1997 (doi:10.1093/aje/kwm042) 2003 Nature (doi:10.1161/01.CIR.0000158483.13093.9D) (doi:10.1016/j.biopha.2015.07.025) 13 17 Nutrients 2000 807–813. (doi:10.1016/S0140-6736(89)90710-1) Journal ofAnimalPhysiologyandNutrition Journal (doi:10.1111/j.1439-0396.2008.00812.x) (doi:10.1007/s40618-015-0413-5) 24–38. Journal ofPregnancy Journal (doi:10.1096/fj.15-280800) 408 American Journal ofEpidemiology American Journal 2015 Downloaded fromBioscientifica.com at09/26/202101:56:54AM Atherosclerosis (doi:10.1002/jbt.10058) 239–247. (doi:10.1016/S0899-9007(97)00193-7) Journal ofBiochemicalandMolecular Journal BMJ Journal ofEndocrinologicalInvestigation Journal 7 Biomedicine andPharmacotherapy 2010 9492–9507. 1989 2010 (doi:10.1038/35041687) 49 Journal ofPhysiology Journal 298 2012 2014 1603–1616. 42 564–567. 176 245–253. (doi:10.3390/ 2012 Circulation www.eje-online.org 237 :2 208–219. FASEB Journal 582748.

(doi:10.1136/ (doi:10.1016/ (doi:10.3858/ 2007 2005 2005 et al. Lancet R93 166 111 2015 2015

565

via freeaccess

European Journal of Endocrinology

www.eje-online.org 57 46 45 59 58 55 54 53 52 51 50 49 48 47 44 56 Review

Mohanty P, Ghanim H,Hamouda W, Aljada A, Garg R&Dandona P. Mohanty P, Hamouda W, Garg R,Aljada A, Ghanim H&Dandona P. Chiva-Blanch G, Urpi-Sarda M,Llorach R, Rotches-Ribalta M, Ghanim H, Sia CL,Upadhyay M,Korzeniewski K,Viswanathan P, Dickinson S, Hancock DP, Petocz P, Ceriello A&Brand-Miller J. Teng KT, Chang CY, Chang LF&Nesaretnam K.Modulationof Peairs AD, Rankin JW&Lee YW. Effectsofacuteingestion polyunsaturatedfatty James MJ, Gibson RA&Cleland LG.Dietary Siri-Tarino PW, Sun Q,Hu FB&Krauss RM.Saturatedfat, Rizza W, Veronese N &Fontana L.What are therolesofcalorie Dandona P, Mohanty P, Hamouda W, Ghanim H,Aljada A,Garg R Dandona P, Mohanty P, Ghanim H,Aljada A,Browne R, Wallace JP, Johnson B,Padilla J&Mather K.Postprandiallipaemia, Ceriello A &Motz E.Isoxidativestressthepathogenicmechanism Aljada A, Mohanty P, Ghanim H,Abdo T, Tripathy D, Chaudhuri A Sen S &Simmons RA.Maternalantioxidantsupplementation mononuclear cells. reactive oxygenspeciesbypolymorphonuclearleukocytesand Both lipidandproteinintakesstimulateincreasedgenerationof Metabolism generation byleucocytes. Glucose challengestimulatesreactiveoxygenspecies(ROS) 2010 Corella D Guillen M, Casas R,Arranz S,Valderas-Martinez P, Portoles O, ajcn.2009.28584) ofClinicalNutrition American Journal and preventsendotoxinincrease Toll-like receptorexpression. effectofahigh-fat,high-carbohydrate meal the proinflammatory Abuaysheh S, Mohanty P&Dandona P. Orangejuiceneutralizes ofClinicalNutrition American Journal activation inmononuclearcellsofyoung,leanhealthysubjects. High-glycemic indexcarbohydrateincreasesnuclearfactor-kappaB evidence. fats:mechanisms andclinical obesity-induced inflammationbydietary 2891-10-122) and obeseadults. different fatsonoxidativestressandinflammationinoverweight Clinical Nutrition mediatorproduction. acids andinflammatory Nutrition carbohydrate, andcardiovasculardisease. Research Reviews restriction anddietqualityinpromotinghealthylongevity? and Metabolism and meta-tyrosineconcentrations. species (ROS)generationbyleucocytesandplasmaortho-tyrosine & Kumar V. effectofatwodayfastonreactiveoxygen Inhibitory Metabolism and proteincarbonylation. of reactiveoxygenspeciesbyleukocytes,lipidperoxidation, restrictionandweightlossintheobeseongeneration of dietary Hamouda W, Prabhala A,Afzal A&Garg R.Thesuppressiveeffect 1241.2009.02146.x) ofClinicalPractice Journal oxidative stressandendothelialfunction:areview. ATV.0000122852.22604.78) Thrombosis andVascular Biology disease? Thecommonsoilhypothesisrevisited. underlying insulinresistance,diabetes,andcardiovascular Clinical Nutrition effect. meal: evidenceforaproinflammatory decrease ininhibitorkappaBmononuclearcellsafteramixed & Dandona P. IncreaseinintranuclearnuclearfactorkappaBand 767–772. prevents adiposityintheoffspringofWestern diet-fedrats. 59 3058–3065. 2010 Nutrition Journal et al. 2001 2000 91 Differentialeffectsofpolyphenolsand alcoholofred 2001 2014 2000 2004 85 86 502–509. Nutrition Journal American Journal ofClinicalNutrition American Journal 355–362. 2970–2973. (doi:10.2337/db10-0301) 86 13 79 71 2899–2902. 38–45. 2014 2010 343S–348S. 682–690. Journal ofClinicalEndocrinologyand Journal Journal ofClinicalEndocrinologyand Journal (doi:10.3945/ajcn.2008.26285) (doi:10.1210/jc.86.1.355) 13 2004 64 (doi:10.1210/jcem.85.8.6854) (doi:10.1016/j.arr.2013.11.002) 12. 2011 389–403. Journal ofClinicalEndocrinology Journal 2010 2008 (doi:10.1210/jcem.86.6.7745) 24 and others E Diamanti-Kandarakis (doi:10.1186/1475-2891-13-12) 816–823. 10 American Journal ofClinical American Journal 91 122. 87 (doi:10.1111/j.1742- 940–949. American Journal of American Journal 1188–1193. American Journal of American Journal Arteriosclerosis Arteriosclerosis (doi:10.1186/1475- (doi:10.1161/01. International International (doi:10.3945/ 2002 Diabetes Ageing 75

Nutrition andoxidativestress 65 62 61 60 70 64 73 72 69 68 67 66 63 71

Bloomer RJ &Fisher-Wellman KH. Systemicoxidativestressis Ceriello A, Bortolotti N,Motz E,Lizzio S,Catone B,Assaloni R, Natella F, Belelli F, Gentili V, Ursini F&Scaccini C.Grapeseed Murphy MP. Howmitochondria producereactiveoxygenspecies. Elosua R, Molina L,Fito M,Arquer A,Sanchez-Quesada JL, Goto C, Nishioka K,Umemura T, Jitsuiki D,Sakagutchi A, Elizalde M, Ryden M,vanHarmelen V, Eneroth P, Gyllenhammar H, Han CY, Umemoto T, Omer M,DenHartigh LJ, Chiba T, LeBoeuf R, Mahadev K, Motoshima H,Wu X, Ruddy JM,Arnold RS,Cheng G, Le Lay S,Simard G,Martinez MC&Andriantsitohaina R.Oxidative Greenberg AS &Obin MS.Obesityandtheroleofadiposetissuein Diamanti-Kandarakis E, Katsikis I,Piperi C,Alexandraki K& Uribarri J, Stirban A,Sander D,Cai W, Negrean M,Buenting CE, Bloomer RJ, Ferebee DE,Fisher-Wellman KH, & Quindry JC consumption ofahighfatmeal. increased toagreaterdegreeinyoung,obesewomenfollowing (doi:10.1046/j.1365-2362.2001.00818.x) diabetes. pleasant approachtothepreventionofcardiovasculardiseasein meal-induced oxidativestressandthrombosisactivation:a Tonutti L &Taboga C. Redwineprotectsdiabeticpatientsfrom 7720–7725. in humans. proanthocyanidins preventplasmapostprandialoxidativestress ajcn.111.022889) ofClinicalNutrition American Journal cytokines relatedtoatherosclerosis:arandomizedclinicaltrial. wine ontheexpressionofadhesionmoleculesandinflammatory Biochemical Journal (doi:10.1155/2014/908539) 2009 stress biomarkerstoa16-weekaerobicphysicalactivityprogram, Covas MI, Ordonez-Llanos J&Marrugat J.Responseofoxidative Hypertension in nitricoxidebioavailiabilityhumans. moderate-intensity exercise inducesvasodilationthroughanincrease Kawamura M, Chayama K,Yoshizumi M &Higashi Y. Acute Longevity and obesehumans. nitric oxidesynthasesinsubcutaneous adiposetissueofnonobese Holm C, Ramel S,Olund A,Arner P & Andersson K.Expressionof Chemistry chemotactic factorgenesincultured adipocytes. derived reactiveoxygenspeciesincreasesexpressionofmonocyte Buller CL, Sweet IR,Pennathur S,Abel ED Biology integral roleininsulinsignaltransduction. modulates insulin-stimulatedgenerationofH Lambeth JD &GoldsteinBJ.TheNAD(P)HoxidasehomologNox4 view. stress andmetabolicpathologies:fromanadipocentricpointof 2006 inflammation andmetabolism. j.1365-2265.2006.02693.x syndrome. advanced glycationend-productsinwomenwithpolycysticovary Panidis D. Effectoflong-termorlistattreatmentonserumlevels (doi:10.2337/dc07-0320) diabetic andnondiabeticsubjects. glycation endproductsacutelyimpairsendothelialfunctionin Koschinsky T &Vlassara H.Singleoralchallengebyadvanced exercise trainingstatus. Schilling BK. Postprandialoxidativestress:influenceofsexand 9150(03)00018-2) women. and toacutephysicalactivity, inhealthyyoungmenand 83 Oxidative MedicineandCellularLongevity 41 2004 461S–465S. 2111–2119. Atherosclerosis 2009 European Journal ofClinicalInvestigation European Journal 2012 Clinical Endocrinology 2007 Journal ofAgriculturalandFoodChemistry Journal (doi:10.1021/jf020346o) 24 2 1844–1854. 287 19–25. 20 2009 10379–10393. Journal ofLipidResearchJournal 825–830. (doi:10.1249/MSS.0b013e3181a9e832) 2003 (doi:10.4161/oxim.2.1.7860) 417 Medicine and Science in Sports andExerciseMedicine andScienceinSports ) Downloaded fromBioscientifica.com at09/26/202101:56:54AM (doi:10.1128/MCB.24.5.1844-1854.2004) 167 1–13. (doi:10.1016/j.amjhyper.2007.02.014) American Journal ofClinicalNutrition American Journal 2007 327–334. Oxidative MedicineandCellular Diabetes Care (doi:10.1074/jbc.M111.304998) (doi:10.1042/BJ20081386) 2012 66 103–109. American Journal of of American Journal 95 et al. Molecular and Cellular Molecular andCellular 176 (doi:10.1016/S0021- 2000 326–334. 2 2014 O NADPHoxidase- :2 2 2007 and plays an andplaysan 2001 Journal ofBiological Journal 41 ( 2014 1244–1251. doi:10.1111/ 2002 30 31 (doi:10.3945/ 2579–2582. 908539. 322–328. 50

R94 via freeaccess

European Journal of Endocrinology

89 81 88 86 85 84 83 82 80 79 78 77 76 75 74 87 Review

Du X, Matsumura T, Edelstein D,Rossetti L,Zsengeller Z,Szabo C Corpeleijn E, Saris WH&Blaak EE.Metabolic flexibilityinthe Galgani JE, Moro C&Ravussin E.Metabolicflexibilityandinsulin Dimitriadis G, Mitrou P, Lambadiari V, Maratou E&Raptis SA. DeFronzo RA, Gunnarsson R,Bjorkman O,Olsson M&Wahren J. Murdolo G, Piroddi M,Luchetti F, Tortoioli C, Canonico B, Furukawa S, Fujita T, Shimabukuro M,Iwaki M,Yamada Y, Donath MY. Targeting inflammationinthetreatmentoftype Meneses ME, Camargo A,Perez-Martinez P, Delgado-Lista J, Cruz-Teno C, Perez-Martinez P, Delgado-Lista J, Travers RL, Motta AC,Betts JA&Thompson D.Adiposetissue Magne J, Mariotti F, Fischer R,Mathe V, Tome D &Huneau JF. Herieka M &Erridge C.High-fatmealinducedpostprandial Little SA &deHaen C.Effectsofhydrogenperoxideonbasaland Krieger-Brauer HI, Medda PK&Kather H.Insulin-inducedactivation May JM &deHaen C.Insulin-stimulatedintracellularhydrogen & Brownlee M.InhibitionofGAPDH activitybypoly(ADP-ribose) j.1467-789X.2008.00544.x) lifestyle. development ofinsulinresistanceand type2diabetes:effectsof 2008 resistance. S0168-8227(11)70014-6) Clinical Practice Insulin effectsinmuscleandadiposetissue. Clinical Investigation in noninsulin-dependent(typeII)diabetesmellitus. Effects ofinsulinonperipheralandsplanchnicglucosemetabolism 95 dysregulation andobesity-linkedinsulinresistance. peroxidation by-productsatthecrossroadbetweenadiposeorgan Zerbinati C, Galli F&Iuliano L.Oxidativestressandlipid 1752–1761. on metabolicsyndrome. Shimomura I. Increasedoxidativestressinobesityanditsimpact Nakajima Y, Nakayama O,Makishima M,Matsuda M& 465–476. 2 diabetes:timetostart. mnfr.201100200) Nutrition andFoodResearch models. syndrome aftertheintakeofdifferentdietary responseinadiposetissueofpatientswithmetabolic inflammatory Gutierrez-Mariscal FM, Tinahones FJ, Vidal-Puig A Cruz-Teno C, Jimenez-Gomez Y, Paniagua JA, Food Research metabolic syndrome:theLIPGENEstudy. stateinsubjectswith fat modifiesthepostprandialinflammatory Jimenez-Gomez Y, Camargo A,Rodriguez-Cantalejo F Yubero-Serrano EM, Garcia-Rios A, Marin C,Gomez P, (doi:10.1007/s00394-015-1087-7) andobesemen. overweight responsestoamixedmealinlean, metabolic andinflammatory jnutbio.2009.03.004) ofNutritionalBiochemistry Journal in healthyrats:possibleinvolvementofvisceraladiposetissue. Early postprandiallow-gradeinflammationafterhigh-fatmeal 136–146. inflammation. 1980 the mechanismofactioninsulin. hormone-stimulated lipolysisinperifusedratfatcellsrelationto 1997 membranes ismediatedbyGalphai2. of NADPH-dependentH Chemistry peroxide productioninratepididymalfatcells. 585–594. 295 255 272 Obesity Reviews E1009–E1017. 1979 10888–10895. 10135–10143. (doi:10.1002/mnfr.201300104) (doi:10.1038/nrd4275) American Journal ofPhysiology:EndocrinologyandMetabolism American Journal (doi:10.1172/jci21625) (doi:10.1016/j.biochi.2012.12.014) 2012 Molecular NutritionandFoodResearch 2011 254 56 2214–2220. 1985 93 854–865. 2009 (Supplement1)S52–S59. 2 (doi:10.1152/ajpendo.90558.2008) Nature Reviews Drug Discovery Nature ReviewsDrug (doi:10.1074/jbc.272.15.10135) O Journal ofClinicalInvestigation Journal 76 2011 2 generationinhumanadipocyteplasma European Journal ofNutrition European Journal 149–155. 10

(doi:10.1002/mnfr.201200096) 178–193. 2010 55 1759–1770. Journal ofBiologicalChemistry Journal and others E Diamanti-Kandarakis Journal ofBiologicalChemistry Journal 21 (doi:10.1172/JCI111938) 550–555. Molecular Nutritionand (doi:10.1111/ Diabetes Research and

Journal ofBiological Journal (doi:10.1002/ (doi:10.1016/ et al. 2014 (doi:10.1016/j. Biochimie Journal of Journal 2014

et al. Molecular 2004 Postprandial 2015.

58 Dietary Dietary 13

114 2013

100 105 104 103 102 101 Nutrition andoxidativestress 95 94 92 91 90 98 93 97 96 99

Martins AR, Nachbar RT, Gorjao R,Vinolo MA, Festuccia WT, Itani SI, Ruderman NB,Schmieder F&Boden G.Lipid-induced Tumova J, Andel M&Trnka J. Excessoffreefattyacidsasacause Summers SA. Ceramidesininsulinresistanceandlipotoxicity. Cooney GJ, Thompson AL,Furler SM,Ye J &Kraegen EW. Lewis GF, Carpentier A,Adeli K&Giacca A.Disorderedfatstorage andmolecularcellbiologyofdiabetic Brownlee M. Biochemistry Pagel-Langenickel I, Bao J, Pang L & Sack MN. The role of mitochondria Pagel-Langenickel I, Bao J,Pang L&Sack MN.Theroleofmitochondria Wang S &Kaufman RJ.Theimpactoftheunfoldedprotein response Yuzefovych LV, Musiyenko SI,Wilson GL &Rachek LI.Mitochondrial damage inendothelialcells. polymerase activatesthreemajorpathwaysofhyperglycemic resistance induced by fatty acids: importance of the mitochondrial resistance inducedbyfattyacids:importanceofthemitochondrial Hirabara SM. Mechanismsunderlyingskeletalmuscleinsulin Lambertucci RH, Cury-Boaventura MF, Silveira LR,Curi R& 51 diacylglycerol, proteinkinaseC,andIkappaB-alpha. insulin resistanceinhumanmuscleisassociatedwithchanges 65 metabolic dysfunctioninskeletalmuscle. in LipidResearch (doi:10.1111/j.1749-6632.2002.tb04276.x) Annals oftheNewYork AcademyofSciences Muscle long-chainacylCoAestersandinsulinresistance. edrv.23.2.0461) type 2diabetes. and mobilizationinthepathogenesisofinsulinresistance complications. 112 Chang Z, Tripathy D, Jani R,Molina-Carrion M Endocrine Reviews in thepathophysiologyofskeletalmuscleinsulinresistance. (doi:10.1083/jcb.201110131) on humandisease. e54059. in highfatdiet-inducedinsulinresistancemice. with endoplasmicreticulumstress,proteindegradationandapoptosis DNA damageanddysfunction,oxidativestressareassociated 511X-11-30) function. ecl.2008.09.002) America Metabolism ClinicsofNorth and muscletheinsulinresistance syndrome. 397–401. human hepatocytes. et al. Cappello D, Dibenedetto A,Carnelutti A,Bonasia V, Pagano C 32345–32353. alcoholic fattyliverdisease. & Shulman GI.Mechanismofhepaticinsulinresistanceinnon- 193–205. in type2diabetes. metabolic mechanismsofinsulinresistanceandbeta-cellfailure Diabetes inskeletal muscle. for mitochondrialoxidativephosphorylation Smith SR. Ahigh-fatdietcoordinatelydownregulatesgenesrequired 295 ofPhysiology:EndocrinologyandMetabolism American Journal lipotoxicity, mitochondrialdysfunction,andinsulinresistance. action ofFA metabolitesonATP synthesis: possiblelinkbetween Abdul-Ghani MA, Muller FL,Liu Y, Chavez AO,Balas B,Zuo P, Lara-Castro C &Garvey WT. Intracellularlipid accumulation inliver Soardo G, Donnini D,Domenis L,Catena C,DeSilvestri D, Samuel VT, Liu ZX,Qu X,Elder BD,Bilz S,Befroy D,Romanelli AJ Muoio DM &Newgard CB.Mechanismsofdisease:molecularand Sparks LM, Xie H,Koza RA,Mynatt R,Hulver MW, Bray GA& 2005–2011. 193–207. E678–E685. 1049–1057. Oxidativestressisactivatedbyfreefattyacidsincultured 2005 (doi:10.1371/journal.pone.0054059) Lipids inHealthandDisease (doi:10.1089/met.2010.0140) (doi:10.1038/nrm2327)

54 (doi:10.1074/jbc.M313478200) Nature (doi:10.2337/diabetes.51.7.2005) 2006 Endocrine Reviews 2010 (doi:10.1152/ajpendo.90287.2008) 1926–1933. (doi:10.1172/JCI18127) Nature ReviewsMolecularCellBiology Journal ofCellBiology Journal Metabolic Syndrome and RelatedDisorders 45 2001 31 42–72. 25–51. Downloaded fromBioscientifica.com at09/26/202101:56:54AM 414 Journal ofBiologicalChemistry Journal (doi:10.2337/diabetes.54.7.1926) Journal ofClinicalInvestigation Journal (doi:10.1016/j.plipres.2005.11.002) 813–820. (doi:10.1210/er.2009-0003) 2002 2008 2012 23 2012 37 2002 11 201–229. Physiological Research (doi:10.1038/414813a) 176 841–856. 30. www.eje-online.org 197 :2 PLoS ONE 967 et al. (doi:10.1186/1476- Endocrinology and 857–867. 196–207. (doi:10.1210/ Deleterious Diabetes (doi:10.1016/j. 2008 2013 2004

2008 2011 9 2002 2003 Progress R95

2015 8 279 via freeaccess

9

European Journal of Endocrinology www.eje-online.org 121 119 118 117 115 114 113 112 111 110 109 107 106 120 108 116 Review

Mattingly KA, Ivanova MM,Riggs KA,Wickramasinghe NS, Zhu L, Martinez MN,Emfinger CH,Palmisano BT&Stafford JM. Nowotny K, Jung T, Hohn A,Weber D &Grune T. Advancedglycation Filipovska A. Estrogen-mediatedregulation ofmitochondrialgene Endocrinology factor-1and increasesmitochondrialbiogenesis. respiratory Barch MJ &Klinge CM.Estradiolstimulatestranscriptionof nuclear Endocrinology transport andgenerationofreactiveoxygenspecies. expression, includinggenesinvolvedinmitochondrialelectron alpha andbetamediatedistinctpathwaysofvasculargene Bienkowska J, Mendelsohn ME&Hansen U.Estrogenreceptors Interventions mitochondria: anewparadigmforvascularprotection? (doi:10.1210/en.2009-1107) cell failureinmetabolicdiseases. Metabolism male micewithobesity. Estrogen signalingpreventsdiet-inducedhepaticinsulinresistancein japplphysiol.00121.2013) ofAppliedPhysiology(1985) Journal ovariectomized rats:atimecoursestudyindifferentfibertypes. Role ofestrogenonskeletalmusclemitochondrialfunctionin Messeder D, Werneck-de-Castro JP, Galina A&Carvalho DP. (doi:10.1152/ajpendo.00189.2009) Physiology: EndocrinologyandMetabolism skeletal muscleandwhiteadiposetissue. Participation ofERalphaandERbetainglucosehomeostasis 193–200. and function. Diabetes Research regulator ofinsulinactionandmitochondrialfunction. jama.295.11.1288) and meta-analysis. sex hormonesandriskoftype2diabetes:asystematicreview 291X(02)02832-2) Research Communications secretion bypancreaticbeta-cells. et al. Hirashima Y, Kawashima J,Shirotani T, Ichinose K,Brownlee M S0026-0495(00)80021-9) glucose concentration. cells topalmitateisdependentonthepresenceofastimulatory of insulingeneexpressionbylong-termexposurepancreaticbeta Biomolecules end productsandoxidativestressintype2diabetesmellitus. (doi:10.2337/diab.46.11.1733) status ofinsulin-producingcells. antioxidant enzymegeneexpressionandantioxidativedefense (doi:10.1074/jbc.274.39.27905) beta cells. mitochondrial activationandinsulinsecretioninpancreatic Sanchez MI, Shearwood AM, Chia T,Sanchez MI, Shearwood AM, Davies SM, Rackham O& O’Lone R, Knorr K,Jaffe IZ,Schaffer ME,Martini PG,Karas RH, Duckles SP, Krause DN,Stirone C &Procaccio V. Estrogenand F.Liu S &Mauvais-Jarvis Minireview:estrogenicprotectionofbeta- Cavalcanti-de-Albuquerque JP, Salvador IC,Martins EL,Jardim- Barros RP, Gabbi C,Morani A,Warner M &Gustafsson JA. Hewitt SC &Korach KS.Estrogenreceptors:structure,mechanisms Gupte AA, Pownall HJ&Hamilton DJ.Estrogen:anemerging Ding EL, Song Y, Malik VS&Liu S.Sexdifferencesofendogenous Sakai K, Matsumoto K,Nishikawa T, Suefuji M,Nakamaru K, Jacqueminet S, Briaud I,Rouault C,Reach G&Poitout V. Inhibition Tiedge M, Lortz S,Drinkgern J&Lenzen S.Relationbetween Maechler P, Jornot L&Wollheim CB. Hydrogenperoxidealters Mitochondrialreactiveoxygenspeciesreduceinsulin (doi:10.1023/A:1020068224909) Journal ofBiologicalChemistry Journal 2014 2015 2006 2008 2007 Reviews inEndocrineandMetabolicDisorders 306 2015 5 6 22 194–222. JAMA 26–35. 21 E1188–E1197. 609–622. 1281–1296. 2015 American Journal of Physiology: Endocrinology and ofPhysiology:Endocrinologyand American Journal Metabolism 2003 2006 (doi:10.1124/mi.6.1.6) 916585. (doi:10.3390/biom5010194) 300 295 (doi:10.1210/me.2007-0029) Diabetes Endocrinology Biochemical andBiophysical 2014 2000 216–222. (doi:10.1152/ajpcell.00096.2013) 1288–1299. (doi:10.1210/me.2006-0497) and others E Diamanti-Kandarakis (doi:10.1155/2015/916585) 1999 2009 116 49 1997 American Journal of American Journal 532–536. 779–789. (doi:10.1016/S0006- 274 297 2010

46 (doi:10.1001/ 27905–27913. E124–E133. 1733–1742. 151 (doi:10.1016/ (doi:10.1152/ Molecular Molecular Journal of Journal 859–864. 2002 Molecular Molecular 3

129 126 125 124 123 122 136 135 134 133 132 131 130 128 127 Nutrition andoxidativestress

obese maleandfemalemice. oxidative stressmarkersinadiposetissuefromweight-matched and Keating AF &Perfield JW2nd.Acomparisonofinflammatory 340–349. atherosclerosis, obesity, anddyslipidemiainfemalemice. The androgenreceptorconfersprotectionagainstdiet-induced De Gendt K,Verhoeven G, Holmang A,Anesten F, Jansson JO pone.0011302) female mice. systemic oxidativestressandpredisposestobeta-cellfailurein jcem.83.8.5041) Endocrinology andMetabolism syndrome. the lipidprofileinpolycysticovary The effectofapureantiandrogenreceptorblocker, flutamide,on (doi:10.1016/0026-0495(95)90062-4) syndrome. with polycysticovary Raptis S. Insulinsensitivityandantiandrogenictherapyinwomen Kaklas N, Spina J,Georgiadou E,Hoffmann RG,Kissebah AH& (doi:10.1210/jc.81.3.952) ofClinicalEndocrinologyand Metabolism Journal treatment: evidencethatandrogensimpairinsulinactioninwomen. with hyperandrogenismispartiallyreversedbyantiandrogen Furlani L, Caputo M&Muggeo M.Theinsulinresistanceinwomen me.2014-1077) expression. Duarte MM, Konopka CK&Emanuelli T. Estrogenplusprogestin (doi:10.1016/j.redox.2013.05.003) enzymes: impactofestrogentherapy. Sexhormones modulatecirculating& Serviddio G. antioxidant 1249–1255. in womenwithperimenopausalsymptoms. Muchova J, Simko M,Waczulikova I &Durackova Z.Oxidativestress ofMedicalandHealthSciences African Journal reproductive, perimenopausalandpostmenopausalphaseoflife. Antioxidant statusandreproductivehormonesinwomenduring 7800.118990) ofMidlifeHealth Journal humupd/8.2.141) ageing. 1326.2011.01488.x) Obesity andMetabolism from adipocyteinflammationandinsulinresistance. Oestrogen altersadipocytebiologyandprotectsfemalemice 2012 stress inwomencomparedwithmen. (doi:10.1161/hq0302.104515) ThrombosisArteriosclerosis andVascular Biology in healthyyoungmencomparedwithpremenopausalwomen. Tsuchihashi M, Tamai H &Takeshita A. Greateroxidativestress Journal Nickelson KJ, Stromsdorfer KL,Pickering RT, Liu TW, Ortinau LC, Fagman JB, Wilhelmson AS, Motta BM,Pirazzi C, Alexanderson C, Liu S, Navarro G&Mauvais-Jarvis F. Androgenexcessproduces Diamanti-Kandarakis E, Mitrakou A,Raptis S,Tolis G &Duleba AJ. Diamanti-Kandarakis E, Mitrakou A,Hennes MM,Platanissiotis D, Moghetti P, Tosi F, Castello R,Magnani CM,Negri C,Brun E, Unfer TC, Figueiredo CG,Zanchi MM, Maurer LH,Kemerich DM, Bellanti F, Matteo M,Rollo T, De Rosario F, Greco P, Vendemiale G Zitnanova I, Rakovan M, Paduchova Z, Dvorakova M, Andrezalova L, Ogunro PS, Bolarinde AA,Owa OO,Salawu AA&Oshodi AA. Theroleofoxidativestressinmenopause. Doshi SB &Agarwal A. te Velde ER &Pearson PL.Thevariabilityoffemalereproductive Stubbins RE, Najjar K,Holcomb VB,Hong J&Nunez NP. Bloomer RJ &Fisher-Wellman KH. Lowerpostprandial oxidative Ide T, Tsutsui H, Ohashi N,Hayashidani S,Suematsu N, 859395. 2015 Human Reproduction Update (doi:10.1016/j.genm.2010.07.001) Molecular Endocrinology (doi:10.1097/gme.0b013e318224fa3d) 29 PLoS ONE (doi:10.1155/2012/859395) 1540–1550. 2010 2013 2012 Downloaded fromBioscientifica.com at09/26/202101:56:54AM 1998 (doi:10.1096/fj.14-259234) 5 Experimental DiabetesResearch 4 14 e11302. 140–146. 58–66. Metabolism 2015 2002 83 2699–2705. Redox Biology Gender Medicine (doi:10.1371/journal. 29 8 (doi:10.1111/j.1463- (doi:10.4103/0976- 141–154. 176 14–27. 2014 1995 Menopause 2002 1996 :2 43 (doi:10.1210/ 44 2013 Journal ofClinical Journal (doi:10.1210/ 22 (doi:10.1093/ 49–57. 81 525–531. 2010 438–442. 2011 952–960. Diabetes, 1 340–346. FASEB 2012 7 18

R96 et al. via freeaccess

European Journal of Endocrinology 152 151 150 149 148 147 145 144 143 142 140 139 138 137 141 146 Review

Ruder EH, Hartman TJ, Blumberg J & Goldman MB. Oxidative stress Ruder EH, Hartman TJ,Blumberg J&Goldman MB.Oxidativestress Pentti K, Tuppurainen MT, Honkanen R,Sandini L,Kroger H, 345–352. IVF/ICSI pregnancy. Elevated bloodplasmaantioxidantstatus isfavourableforachieving 011.579652) Gynecological Endocrinology stress parametersonintracytoplasmicsperminjectionoutcome. &Falcone T.Arrigain S, Agarwal A Effectoffollicularfluidoxidative 973–976. of assistedreproductiveprocedures. & Rose BI. Effectofoxidativestressinfollicularfluidontheoutcome Toxicology endometriosis andtubalinfertilityundergoingIVF. Markers ofoxidativestressinfollicularfluidwomenwith 2006 qualitymarkerinIVF? follicular fluid–embryo Reactiveoxygenspecieslevelin Chakravarty BN &Chaudhury K. Online compared withfertileoocytedonors. stress infollicularfluidofyoungwomenwithlowresponse Vara E, Ortega L,Caballero P, Rancan L&Tresguerres J. Oxidative Reproduction Update and antioxidants:exposureimpactonfemalefertility. 175–189. embryo anditssurroundings. embryo protection againstreactiveoxygenspeciesinthepre-implantation (doi:10.1095/biolreprod49.5.918) interaction ofgametes. S40–S42. the ovary. 553–558. on diabetesandrisk. of Endocrinology Kuopio osteoporosisriskfactorandpreventionstudy. Alhava E &Saarikoski S.Hormonetherapyprotectsfromdiabetes:the Endocrinology from high-fatdiet-inducedhepaticandmuscleinsulinresistance. mechanism bywhichestradiolprotectsfemaleovariectomizedmice Samuel VT, Petersen KF, Carvalho CR, Jurczak MJ Gerontology fed withhighfatdiet:themolecularmechanisms. isoflavones (fromGlycinemax)inovariectomized Wistar rats Amelioration ofoxidativestressandinsulinresistancebysoy 227 effect ofahighsucrosediet. syndrome intherat:femalesareprotectedagainstpro-oxidant (doi:10.1155/2014/204390) transition inhealthywomen. 13697137.2014.964669) postmenopausal women. increase superoxidedismutaseandtotalantioxidantcapacityin Velthut A, Zilmer M,Zilmer K,Kaart T, Karro H&Salumets A. Bedaiwy MA, Elnashar SA,Goldberg JM,Sharma R,Mascha EJ, Sharma RK,Izzo VM,Pinotti JA, Joshi NJ Pasqualotto EB, Agarwal A, Singh AK, Chattopadhyay R,Chakravarty B&Chaudhury K. Das S, Chattopadhyay R,Ghosh S,Goswami SK, Nunez-Calonge R, Cortes S,GutierrezGonzalez LM,Kireev R, Guerin P, ElMouatassim S&Menezo Y. Oxidativestressand Miesel R, Drzejczak PJ&Kurpisz M.Oxidativestressduringthe Behrman HR, Kodaman PH,Preston SL&Gao S.Oxidativestressand Szmuilowicz ED, Stuenkel CA&Seely EW. Influenceofmenopause Camporez JP, Jornayvaz FR,Lee HY, Kanda S, Guigni BA,Kahn M, Sankar P, Zachariah B,Vickneshwaran V, Jacob SE&Sridhar MG. Busserolles J, Mazur A,Gueux E,Rock E&Rayssiguier Y. Metabolic Moreau KL &Hildreth KL.Vascular agingacrossthemenopause 837–842. 21 2016 2403–2407. (doi:10.1016/S1071-5576(00)00106-4) (doi:10.1016/j.rbmo.2012.12.012) (doi:10.1016/j.fertnstert.2003.11.021) (doi:10.1093/humupd/7.2.175) (doi:10.1038/nrendo.2009.166) 2013 Journal oftheSocietyforGynecologicInvestigation Journal 2015 32 2013 2009 446–456. 42 63 2008 116–124. 154 67–75. Reproductive Biomedicine Online (doi:10.1093/humrep/del156) 160 1021–1028. Biology ofReproduction 14 979–983. Climacteric (doi:10.1016/j.rbmo.2015.12.010) 2012 345–357. (doi:10.1016/j.exger.2015.02.001) Experimental BiologyandMedicine (doi:10.1016/j.reprotox.2013.08.005) Nature ReviewsEndocrinology Advances inVascular Medicine Human Reproduction Update 28 (doi:10.1530/EJE-09-0151) 51–55. (doi:10.1210/en.2012-1989) Fertility andSterility Fertility 2015 (doi:10.1093/humupd/dmn011) and others E Diamanti-Kandarakis Reproductive Biomedicine 18 (doi:10.3109/09513590.2 379–388. 1993 Human Reproduction et al. Experimental 2013 49 Reproductive European Journal European Journal Cellular 918–923. 2004 (doi:10.3109/ Human Human 2001 26 2001 2009 2014.

2002 81 7 8 5

157 153 161 159 158 156 155 154 168 167 166 164 163 162 160 165 Nutrition andoxidativestress

Carbone MC, Tatone C, Delle Monache S,Marci R, Caserta D, in femalereproduction. 42 oocyte developmentalcompetence. vitro murinefolliclegrowthalterfollicularphysiologyandreduce Leroy JL. Elevatednon-esterifiedfattyacidconcentrationsduringin Cardona AP, Gutierrez-Adan A,Berth M,Cortvrindt R,Bols PE& and clinicalconsequences. 2011 pregnancy byassistedreproductivetechnology. developmentandachievementof compromises embryonic & Miyazaki A.Advancedglycationend-productsaccumulation (doi:10.1093/humrep/det383) glyoxalases inovarianfunction. andSterility ofFertility journal International expenditure relatedfactorsandoxidativestressinfollicularfluid. Nejat SN &Rahimi-Foroshani A.Relationshipbetweenenergy ofReproductive Medicine Iranian Journal qualitybyinducingoxidativestressinfollicularfluid? and embryo fatintakeinfluenceoocytecompetence & Ahmadi M.Doesdietary 1769.e1761–1776.e1761. products (AGEs)andtheirreceptor(RAGE) inpolycysticand Immunohistochemical localization of advancedglycationend- Panidis D, Pawelczyk L,Papavassiliou AG &Duleba AJ. (doi:10.1021/tx1001282) estrogens. via reactiveoxygenspeciesdifferentiatesequineandhuman generating apurinic/apyrimidinicsitesand8-oxo-deoxyguanosine Thatcher GR &Bolton JL.Redoxcyclingofcatecholestrogens Reproduction gene expressiondecreaseswithaginginthemouseovary. Human Reproduction follicular fluid:characterizationandage-dependentchanges. Colonna R &Amicarelli F. Antioxidantenzymaticdefencesinhuman (doi:10.1016/1071-5576(95)00041-0) oocyte. developmental potentialandchromosomalnormalityofthehuman j.maturitas.2005.03.001) and fertilewomen. Behaviour ofsomeindicatorsoxidativestressinpostmenopausal Marchese G, Celotta G,Cassibba N, Pennisi G&Caschetto S. 14 aspects ofovarianfollicleageing. Marci R, Artini PG,Piomboni P &Focarelli R.Cellularandmolecular (doi:10.1210/er.2009-0006) Metabolism indicator ofovarianreserve. receptor foradvancedglycationend-products(sRAGE):apotential Clinical Laboratory study.follicular fluidinassistedreproductivecycles–apreliminary Zima T &Kalousova M.ConcentrationsofsRAGEinserumand Merhi Z. Advancedglycationendproductsandtheirrelevance Valckx SD, Van Hoeck V, Arias-Alvarez M,Maillo V, Lopez- Broekmans FJ, Soules MR&Fauser BC.Ovarianaging:mechanisms Malickova K, Jarosova R,Rezabek K,Fait T, Masata J,Janatkova I, Jinno M, Takeuchi M, Watanabe A, Teruya K, Hirohama J,Eguchi N Tatone C, Eichenlaub-Ritter U&Amicarelli F. Dicarbonylstressand Kazemi A, Ramezanzadeh F, Nasr-Esfahani MH,Saboor-Yaraghi AA, Kazemi A, Ramezanzadeh F, Nasr-Esfahani MH,SaboorYaraghi AA Diamanti-Kandarakis E, Piperi C,Patsouris E, Korkolopoulou P, Wang Z, Chandrasena ER,Yuan Y, Peng KW, vanBreemen RB, Lim J &Luderer U.Oxidativedamageincreasesandantioxidant Van Blerkom J.Theinfluenceofintrinsicandextrinsicfactorsonthe Signorelli SS, Neri S,Sciacchitano S,Pino LD,Costa MP, Tatone C, Amicarelli F, Carbone MC,Monteleone P, Caserta D, Merhi Z, Irani M,Doswell AD&Ambroggio J.Follicularfluidsoluble 433–438. 131–142. 26 Journal oftheSocietyforGynecologicInvestigation Journal 604–610. Chemical Research inToxicology 2014 2011 (doi:10.1042/BST20140023) (doi:10.1093/humupd/dmm048) 99 2010 84 (doi:10.1093/humrep/deq388) 2003 E226–E233. Maturitas 775–782. 56 Human Reproduction 9 (doi:10.1016/j.fertnstert.2014.08.018) Downloaded fromBioscientifica.com at09/26/202101:56:54AM 639–643. 377–384. Endocrine Reviews Journal ofClinicalEndocrinologyand Journal 2006 (doi:10.1095/biolreprod.110.088583) Biochemical SocietyTransactions (doi:10.1210/jc.2013-3839) Human Reproduction Update 53 Fertility andSterility Fertility (doi:10.1093/molehr/gag090) 2013 77–82. 2010 2014 176 2014 11 2009 www.eje-online.org (doi:10.1016/ 1005–1012. :2 23 8 Human Reproduction 175–182. 1365–1373. 29 30 135–145. 465–493. 1996 2014 Biology of Molecular Molecular

2008 3 102 R97 3–11. 2014 via freeaccess

European Journal of Endocrinology 173 172 182 181 www.eje-online.org 184 183 179 178 177 176 175 174 171 170 169 180 Review

Murri M, Luque-Ramirez M,Insenser M,Ojeda-Ojeda M&Escobar- Sterility of womenwithendometriosisoridiopathicinfertility. Importance ofreactiveoxygenspeciesintheperitonealfluid 2001 ofObstetricsandGynecologyReproductiveEuropean Biology Journal Total antioxidantstatusofperitonealfluidininfertilewomen. polycystic ovary syndrome. polycystic ovary Oxidative stressandinflammationinleanobesesubjectswith ofReproductive Medicine Iranian Journal syndrome. defense systeminIranianwomenwithpolycysticovary Masoomikarimi M &Jafarisani M.Oxidativestressandanti-oxidant Camps J. Paraoxonase-1infemaleinfertility: apossibleroleagainst 0412.2011.01337.x) Gynecologica Scandinavica syndrome. in womenwithpolycysticovary glutathione peroxidaseactivities,nitric oxideandthiollevels Kaya T. Assessmentofparaoxonase1,xanthineoxidaseand 107–114. Reproduction Update syndrome(PCOS):asystematicreviewandmeta-analysis. ovary Morreale HF. Circulating markers ofoxidativestressandpolycystic 2709–2722. syndrome. polycystic ovary (doi:10.1016/j.ejogrb.2015.05.005) Obstetrics andGynecologyReproductive Biology complications inpolycysticovariansyndrome. and Sterility er.2011-1034) implications. syndromerevisited:anupdateonmechanismsand polycystic ovary 1999 and metabolicprofile. syndromeintheGreekislandofLesbos:hormonal polycystic ovary Tsianateli TC, ofthe Spina GG,Zapanti ED&Bartzis MI.Asurvey 86 randomized double-blindcontrolledtrial. ovulation inthemanagementofunexplainedinfertility:a plus N-acetylcysteineversusclomiphenecitrateforaugmenting ofBiologicalRegulatorsandHomeostatic Agents Journal glycation endproductsinovariesofreproductively-agedmice. during ageing:roleofmethylglyoxalintheformationadvanced Talesa V, Focarelli R&Amicarelli F. Femalereproductivedysfunction Human Reproduction end productsandtheirreceptorcontributetoovarianageing. 2460–2469. ovarian tissue. with AGEsignallingtomodulatecollagensynthesisinpolycystic Diamanti-Kandarakis E &Papavassiliou AG.Lysyl oxidaseinteracts (doi:10.1007/s00418-006-0265-3) normal ovaries. Wang Y, Sharma RK,Falcone T, Goldberg J&Agarwal A. Polak G, Koziol-Montewka M,Gogacz M,Blaszkowska I&Kotarski J. Blair SA, Kyaw-Tun T, Young IS, Phelan NA,Gibney J&McEneny J. Moti M, Amini L,MirhoseiniArdakani SS,Kamalzadeh S, Marsillach J, Checa MA,Pedro-Botet J, Carreras R,Joven J& Baskol G, Aygen E, Erdem F, Caniklioglu A,Narin F, Sahin Y& Papalou O, Victor VM &Diamanti-Kandaraki E.Oxidativestressin Hyderali BN &Mala K.Oxidativestressandcardiovascular process? Duleba AJ &DokrasA.IsPCOSaninflammatory Diamanti-Kandarakis E &Dunaif A.Insulinresistanceandthe Diamanti-Kandarakis E, Kouli CR,Bergiele AT, Filandra FA, Badawy A, BakerElNasharA&Totongy M.Clomiphenecitrate Tatone C, Carbone MC,Campanella G,Festuccia C,Artini PG, Stensen MH, Tanbo T, Storeng R&Fedorcsak P. Advancedglycation Papachroni KK, Piperi C,Levidou G,Korkolopoulou P, Pawelczyk L, 647–650. 84 94 1997 4006–4011. 261–263. 2012 (doi:10.1111/j.1582-4934.2009.00841.x) (doi:10.2174/1381612822666160216151852) (doi:10.1016/j.fertnstert.2006.02.097) Endocrine Reviews 68 Journal ofCellularandMolecularMedicine Journal Histochemistry andCellBiology Histochemistry 826–830. 97 2013 (doi:10.1016/S0301-2115(00)00352-3) 2014 7–12. (doi:10.1210/jcem.84.11.6148) Journal ofClinicalEndocrinologyandMetabolism Journal 19 2012 29 (doi:10.1016/j.fertnstert.2011.11.023) 268–288. (doi:10.1016/S0015-0282(97)00343-9) Current Pharmaceutical Design Current Pharmaceutical Journal ofReproductive Medicine Journal 125–134. 2012 91 326–330. 33 (doi:10.1093/humupd/dms059) and others E Diamanti-Kandarakis 2015 (doi:10.1093/humrep/det419) 981–1030. Fertility andSterility Fertility 13 Acta Obstetriciaet (doi:10.1111/j.1600- 2007 373–378. European Journal of European Journal 2015 (doi:10.1210/ 127 2010 191 2010 581–589. Fertility andFertility 2016 Fertility Fertility 24 15–22. 2013 63–72. 14 2006 Human Human 22

58

189 188 187 186 185 195 194 193 192 190 198 197 196 191 Nutrition andoxidativestress

Malin SK, Kirwan JP, Sia CL&Gonzalez F. Pancreaticbeta-cell promote oxidativestressinleanreproductive-agewomen. Hyperandrogenism sensitizesleukocytestohyperglycemia E297–E306. ofPhysiology:EndocrinologyandMetabolism Journal induced inflammationinleanreproductive-agewomen. Hyperandrogenism sensitizesmononuclearcellstopromoteglucose- horm.2002.1525 syndrome. ovary peroxidase activityinnon-obesewomenwithpolycystic et al. Zarkovic M, Djukic T, Pljesa-Ercegovac M, Panidis D,Katsikis I humrep/des320) syndrome. abdominal adiposityinnormal-weightwomenwithpolycysticovary Hyperglycemia-induced oxidativestressisindependentofexcess (doi:10.1210/jc.2005-1696) ofClinicalEndocrinologyand Metabolism Journal syndrome. resistance andhyperandrogenisminpolycysticovary species-induced oxidativestressinthedevelopmentofinsulin 1132–1134. oxidative stress-inducedinflammation. Oxidative MedicineandCellularLongevity hyperandrogenism-induced murinemodelofpolycysticovary. Baeeri M &Abdollahi M.Ovarianaging-likephenotypeinthe 109/19396368.2012.743197) IVF. Oxidative statusingranulosacellsofinfertilewomenundergoing 17–33. developmental competence. syndrome:impactonoocytematurationandembryo ovary (doi:10.1159/000270900) syndrome. spindle formationininfertilewomenwithpolycysticovarian Effectoffollicularfluidoxidativestressonmeiotic & Chaudhury K. E770–E777. ofPhysiology:EndocrinologyandMetabolism American Journal induced nuclearfactor-kappaBactivationandsystemicinflammation. syndrome:roleofhyperglycemia- dysfunction inpolycysticovary jc.2013-3177) Endocrinology andMetabolism syndrome. cell dysfunctioninpolycysticovary oxidative stressinmononuclearcellsisrelatedtopancreaticbeta- (doi:10.1210/jc.2012-1259) of ClinicalEndocrinologyandMetabolism Papavassiliou AG &Panidis D.Increased serumadvancedglycation jc.2013-2375) Endocrinology andMetabolism syndrome (PCOS):frominuteroto menopause. deq088) Human Reproduction syndromeanexceptionforreproductive aging? polycystic ovary (doi:10.1155/2014/948951) Gonzalez F, Nair KS,Daniels JK,Basal E,Schimke JM&Blair HE. Gonzalez F, Nair KS,Daniels JK,Basal E&Schimke JM. Savic-Radojevic A, BozicAntic I,Coric V, Bjekic-Macut J,Radic T, Gonzalez F, Sia CL,Shepard MK,Rote NS&Minium J. Gonzalez F, Rote NS,Minium J&Kirwan JP. Reactiveoxygen Rezvanfar MA, ShojaeiSaadi HA,Gooshe M,Abdolghaffari AH, Karuputhula NB, Chattopadhyay R,Chakravarty B&Chaudhury K. Qiao J &Feng HL.Extra-andintra-ovarianfactorsinpolycystic Chattopadhayay R, Ganesh A,Samanta J,Jana SK,Chakravarty BN Malin SK, Kirwan JP, Sia CL&Gonzalez F. Glucose-stimulated Diamanti-Kandarakis E, Katsikis I,Piperi C, Kandaraki E,Piouka A, Welt CK &Carmina E. Clinicalreview:lifecycleofpolycysticovary Tehrani FR, Solaymani-Dodaran M, Hedayati M&Azizi F. Is Systems BiologyinReproductive Medicine Effectofhyperglycemiaandhyperinsulinemiaonglutathione (doi:10.1093/humupd/dmq032) Human Reproduction Gynecologic andObstetricInvestigation (doi:10.1152/ajpendo.00510.2014) (doi:10.1016/j.fertnstert.2009.11.043) (doi:10.1152/ajpendo.00416.2011) ) Hormones 2010 25 Downloaded fromBioscientifica.com at09/26/202101:56:54AM 2015 2014 2013 Human Reproduction Update 1775–1781. 2012 14 98 99 101–108. 27 322–329. 4629–4638. 2012 2014 Fertility andSterility Fertility 3560–3568. (doi:10.1093/humrep/ 2013 176 97 2014 ( 2006 doi:10.14310/ :2 Journal ofClinical Journal 2010 (doi:10.1210/ 2836–2843. Journal ofClinical Journal 59 2012 (doi:10.1210/ 948951. 91–98. (doi:10.1093/ 91 69 336–340. 302 2011 197–202. American 2015 Journal Journal 2010 (doi:10.3

R98 17 308

94 via freeaccess

European Journal of Endocrinology 205 204 203 202 201 200 199 Review

stress andantioxidantdefenseinendometriosisitsmalignant syndrome (PCOS). the hormonalandmetabolicprofileofwomenwithpolycysticovary modificationofadvancedglycationendproducts(AGEs)on dietary Koulouri A, Christakou C&Diamanti-Kandarakis E.Impactof pnas.1205847109) and sirtuin1. and diabetesbydepletingtheantioxidantdefensesAGEreceptor-1 advanced glycationendproducts(AGEs)promoteinsulinresistance Medicine and insulinsignalingingranulosacells. Koundouras D &Koutsilieris M.Advancedglycationend-products Medicine excess: acausativelinktopolycysticovariansyndrome. glycotoxinsandandrogen ovarian glyoxalase-Iactivitybydietary Korkolopoulou P, Koutsilieris M&Papavassiliou AG.Reduced (doi:10.1007/s00109-007-0246-6) normal femalerats. glycotoxinsinthereproductivesystemof Accumulation ofdietary Levidou G, Papalois A,Patsouris E&Papavassiliou AG. 160 syndrome. polycystic ovary with advancedglycosylatedendproductsinleanwomen Papavassiliou AG &Panidis D.Anti-mullerianhormoneisassociated (doi:10.1111/j.1365-2265.2008.03247.x) syndrome(PCOS). ovary end-products isadistinctfindinginleanwomenwithpolycystic Iwabuchi T, Yoshimoto C, Shigetomi H&Kobayashi H.Oxidative Tantalaki E, Piperi C,Livadas S,Kollias A,Adamopoulos C, Cai W, Ramdas M,Zhu L,Chen X,Striker GE&Vlassara H.Oral Diamanti-Kandarakis E, Chatzigeorgiou A,Papageorgiou E, Kandaraki E, Chatzigeorgiou A,Piperi C,Palioura E,Palimeri S, Diamanti-Kandarakis E, Piperi C,Korkolopoulou P, Kandaraki E, Diamanti-Kandarakis E, Piouka A,Livadas S,Piperi C,Katsikis I, 847–853. 2012 2015 PNAS (doi:10.1530/EJE-08-0510) 18 241 1183–1189. 1438–1445. Hormones 2012 Journal ofMolecularMedicine Journal Clinical Endocrinology 109 European Journal ofEndocrinology European Journal 2014 15888–15893. ( doi:10.2119/molmed.2012.00293 (doi:10.1177/1535370215584937) 13 65–73. and others E Diamanti-Kandarakis Experimental Biologyand (doi:10.1073/ 2008 2007 69 85 634–641. Molecular 1413–1420. 2009

) Accepted 27September2016 Revised versionreceived20September2016 Received 24July2016 210 209 208 207 206 211 Nutrition andoxidativestress

transformation. 6-month calorierestrictiononbiomarkersoflongevity, metabolic Rood J, Nguyen T, Martin CK,Volaufova J, Most MM (doi:10.1186/1477-7827-7-54) antioxidant diet. peripheral antioxidantmarkersaftertheapplicationofahigh Guerrero C. Women withendometriosisimprovedtheir Zamudio L, Tolentino MC, Casanueva E&Hernandez- REP-14-0438) endometriosis. the intrafollicularthiol-redoxsystemininfertilewomenwith fertnstert.2012.03.052) endometriosis. markers ofoxidativestressinwomenwithinfertilityrelatedto & Garcia-Velasco JA. Analysisoffollicularfluidandserum 0282(02)03333-2) andSterility Fertility lipoprotein andperitonealfluidfromwomenwithendometriosis. peritoneal mesothelial and endometrial cells by oxidized low-density Parthasarathy S. Inductionofmonocytechemotacticprotein-1in 848595. 140. report. 2 diabetes:apreliminary the MediterraneandietonendothelialresistancetoGLP-1intype Bucciarelli L, Rondinelli M&Genovese S.Theprotectiveeffectof (doi:10.1001/jama.295.13.1539) a randomizedcontrolledtrial. individuals: adaptation, andoxidativestressinoverweight Heilbronn LK, deJonge L,Frisard MI,DeLany JP, Larson-Meyer DE, Mier-Cabrera J, Aburto-Soto T, Burrola-Mendez S,Jimenez- Choi YS, Cho S,Seo SK,Park JH,Kim SH&Lee BS.Alterationin Prieto L, Quesada JF, Cambero O,Pacheco A,Pellicer A,Codoceo R Rong R, Ramachandran S,Santanam N,Murphy AA& Ceriello A, Esposito K,LaSala L,Pujadas G,DeNigris V, Testa R, (doi:10.1186/s12933-014-0140-9) (doi:10.1155/2015/848595) Reproduction andSterility Fertility Oxidative MedicineandCellularLongevity Reproductive BiologyandEndocrinology 2002 78 Downloaded fromBioscientifica.com at09/26/202101:56:54AM 2015 843–848. JAMA Cardiovascular Diabetology 149 2012 2006 155–162. (doi:10.1016/S0015- 98 295 176 126–130. www.eje-online.org 1539–1548. :2 (doi:10.1530/ et al. (doi:10.1016/j. 2009 2015 Effectof 2014

R99 7 2015 54. 13 via freeaccess